ANTIRETROVIRAL DRUGS (ARVs)

Definition of terms:

1. Antiviral drug: A general term for any drug that destroys viruses, either directly
or indirectly by suppressing their replication.
2. Antiretroviral Drugs (ARVs): A more specific term for antiviral drugs that
work against retroviruses such as HIV.
3. HIV: Human Immunodeficiency Virus
4. AIDS: Acquired immune deficiency syndrome
5. PEP: Post-exposure prophylaxis. It is for people who have possibly been exposed
to HIV.
6. PrEP: Pre-exposure prophylaxis. It is for people who don't already have HIV but
are at very high risk of getting it.
7. ART: Antiretroviral Therapy
8. HAART: Highly active antiretroviral therapy

Brief History of HIV Infection and The Aids Pandemic

 The origin of HIV is still unknown; but it is widely believed that HIV originated in
Kinshasa in the DRC in around 1920 when HIV crossed species from
chimpanzees to humans. Up until the 1980s, the number of people who were
infected with HIV or had developed AIDS is still unknown.
 The first U.S. cases of AIDS were recognized in 1981 in 31 previously healthy
homosexual men in Los Angeles and New York city.
 The first patients mysteriously developed Pneumocystis carinii pneumonia
(PCP) or Kaposi’s sarcoma, both normally extremely rare illnesses.
 Still in 1981, PCP cases were reported in people who injected themselves with
drugs and in hemophiliac patients who had been transfused blood-derived
clotting factors.
 In 1982, a group of cases among gay men in Southern California suggested that
the cause of the was sexual and the syndrome was initially called Gay-related
immune deficiency (GRID). Later in the same year, the disease was reported in
Haitians leading many to believe that it had originated in Haiti.
 In January 1983, the disease was reported among the female partners of men
who had the disease suggesting it could be passed on via heterosexual sex. Later
the same year, the human T-cell lymphotropic virus type 3 (HTLV-3) was
isolated from a patient with lymphadenopathy (swollen lymph nodes) and in
1984 was demonstrated to be the cause of AIDS. This virus was later renamed
Human Immunodeficiency Virus (HIV). (Read more about the historical
moments that have defined the HIV epidemic at least over the past 35 years).
Types and stages of HIV

There are two recognized types of HIV; both of which cause AIDS

HIV-1: this causes the majority of the HIV pandemic the whole world.

HIV-2: this is primarily localized in west Africa.

In addition to HIV-1 and HIV-2, there are two other retroviruses known to infect
humans: human T-cell lymphotropic virus type 1 (HTLV-1) and human T-cell
lymphotropic virus type 2 (HTLV-2).

According to WHO, there are four stages of HIV infection;

Stage 1: Refers to first few weeks or months after initial exposure to the virus. It’s
characterized by asymptomatic infection. Patients may be asymptomatic but may show
signs of persistent generalized lymphadenopathy (PGL), or swollen lymph nodes.

Stage 2: it’s characterized by early, general symptoms of the disease. It involves

continued lymphadenopathy along with other symptoms, including fever, rash, sore
throat, night sweats, malaise, diarrhea, idiopathic thrombocytopenia, oral candidiasis,
herpes zoster among others. These symptoms may actually resolve spontaneously and
the patient may not have further progression of these symptoms for 1-10yrs. During
this stage, the CD4 + T-cell count begin to drop, while HIV antibody levels rise.

Stage 3: characterized by moderate symptoms, in this stage the infection progresses to

a moderately symptomatic state. Continued weight loss and chronic diarrhea and fever,
CD4+ T-cell count continues to drop. Opportunistic infections begin, including oral
candidiasis(thrush), severe bacterial pneumonias, and pulmonary TB (PTB).

Stage 4: characterized by severe symptoms, often leading to death. It was formally

called full-blown AIDS. Viral replication increases dramatically, resulting in increasing
destruction of helper T cells and a corresponding decrease in CD4 counts. There’s a
major decline in the immune system function. When CD4+ count drops below 200
cells/mm3, multiple, severe opportunistic infections begin to occur. Fever, night sweats,
and malaise resume and are now accompanied by increasingly severe opportunistic
infections such as mycobacterium avium complex (MAC) and pneumocystis jirovecii
pneumonia. Other common OIs include parasitic infections such as cryptosporidial
diarrhea and toxoplasmosis encephalitis; viral infections such as HSV mouth ulcer,
disseminated extrapulmonary TB, esophagitis, pneumonitis, fungal infections such as
candidiasis of the GI and respiratory tracts and invasive aspergillosis of the lungs. Other
conditions in this stage include; Kaposi’s sarcoma, HIV wasting syndrome, chronic
diarrhea, chronic fatigue, constant fevers, HIV-induced encephalopathy and dementia etc.

Death is most likely when CD4+ count falls below 50 cells/mm 3.

Antiretroviral Drugs (ARVs)

Antiretroviral treatment (also known as antiretroviral therapy or ART) are drugs used
in the treatment and management of human immune deficiency virus called the retro-
virus such as HIV. These drugs work by stopping the virus replicating in the body which
allows the immune system to repair itself and prevent further damage. It should be
noted that these drugs do not cure HIV.

ART is recommended for all people with HIV, regardless of how long they’ve had the
virus or how healthy they are. ART also reduces your chance of transmitting HIV to
others if taken as prescribed.

Treatment guidelines external icon from the U.S. Department of Health and Human
Services recommend that a person with HIV begin antiretroviral therapy (ART) as soon
as possible after diagnosis. If you delay treatment, the virus will continue to harm your
immune system and put you at higher risk for developing AIDS, which can be life
threatening.

The goals for these medicines are to:

 Control the growth of the virus

 Improve how well your immune system works

 Slow or stop symptoms

 Prevent transmission of HIV to others

Mode of action.

HIV/AIDS medicines reduce the amount of HIV (viral load) in your body. This helps to:

 Give your immune system a chance to recover. Even though there is still some
HIV in your body, your immune system should be strong enough to fight off
infections and certain HIV-related cancers.

 Reduce the risk that you will spread HIV to others

Classification of Antiretroviral drugs

Currently there are six different classes of antiretroviral drugs used to treat HIV. The
healthcare provider for a person living with HIV will decide on the best medications for
that individual case.

This decision will depend on:

 the person’s viral load

  their T-cell count

 their strain of HIV

 the severity of their case

 how far the HIV has spread

 other chronic health conditions, also known as comorbidities

 other medications that they’re taking to avoid interactions between their HIV
drugs and their other drugs e.g. nasal sprays, inhalers etc.

The classes of antiretroviral drugs include:

1. Integrase inhibitors/ Integrase strand transfer inhibitors (INSTIs)

Mechanism of Action.

Integrase is a viral enzyme that HIV uses to infect T cells by putting HIV DNA into the
human DNA. Therefore, the integrase inhibitors work by blocking the integrase enzyme.

Examples

 Bictegravir or BIC (not available as a stand-alone drug, but available in the

combination drug Biktarvy)
 Dolutegravir or DTG (Tivicay)
 Elvitegravir or EVG (not available as a stand-alone drug, but available in the
combination drugs Genvoya and Stribild)
 Raltegravir or RAL (Isentress, Isentress HD)

2. Protease inhibitors (PIs)

Mechanism of Action.

These drugs work by inhibiting the protease retroviral enzyme.

HIV needs protease to replicate in the body. When protease is blocked and can’t do its
job, the virus can’t complete the process that makes new copies. This reduces the
number of viruses that can infect more cells.

Examples of Protease inhibitors (PIs) used to treat HIV:

 Atazanavir or ATV (Reyataz)

 Darunavir or DRV (Prezista)

 Fosamprenavir or FPV (Lexiva)

  Lopinavir (not available as a stand-alone drug, but available with ritonavir in
the combination drug (Kaletra) or LPV/r

 Ritonavir or RTV (Norvir)

 Tipranavir or TPV (Aptivus)

 Indinavir or IDV (Crixivan)

 Nelfinavir or NFV (Viracept)

 Saquinavir or SQV (Invirase, Fortovase)

PIs are almost always used with either cobicistat or ritonavir, the CYP3A inhibitors.
Note: 1. Ritonavir is both a CYP3A inhibitor and a PI.

2. Ritonavir is often used to boost other HIV medications.

3. Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)

NRTIs are sometimes referred to as “nukes.” They work by interrupting the life cycle of
HIV as it tries to copy itself. They in fact block the reverse transcriptase enzyme. NRTIs
force the HIV virus to use faulty versions of building blocks so infected cells can't make
more HIV.

Examples include the following drugs are NRTIs:

 Abacavir or ABC (Ziagen)  Tenofovir alafenamide fumarate

or TAF (Vemlidy)
 Didanosine, or ddl (Videx)
 Tenofovir Disoproxil
 Emtricitabine or FTC (Emtriva)
Fumarate or TDF (Viread)
 Lamivudine or 3TC (Epivir)
 zidovudine or ZDV (Retrovir)

 Stavudine, or d4T (Zerit)

Note: Zidovudine was the first FDA-approved HIV drug. It’s also known as
azidothymidine or AZT. Zidovudine is rarely used in adults now. It’s mainly given to
babies born to HIV-positive mothers as a form of post-exposure prophylaxis (PEP).

4. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

 These are also called "non-nukes." NNRTIs bind to a specific protein so the HIV
virus can't make copies of itself, similar to jamming a zipper. They do this by binding to
and later change the reverse transcriptase enzyme.

The following drugs are NNRTIs, or “non-nukes”:

  Delavirdine or DLV (Rescripor)  Etravirine or ETR (Intelence)

 Doravirine, or DOR (Pifeltro)  Nevirapine or NVP (Viramune)

 Efavirenz or EFV (Sustiva)  Rilpivirine or RPV (Edurant)

5. Entry inhibitors

Fusion inhibitors, post-attachment inhibitors, and CCR5 antagonists are all a part of a
larger class of HIV drugs known as entry inhibitors. All entry inhibitors work by
blocking the virus from entering healthy T cells. These drugs are rarely used as first-line
treatments for HIV.

5.1 Fusion Inhibitors

Unlike NRTIs, NNRTIs, PIs, and INSTIs -- which work on infected cells -- these drugs help
block HIV from getting inside healthy cells in the first place.

Examples include

Enfuvirtide, or ENF or T-20 (Fuzeon) (only available member)

5.2 Chemokine coreceptor antagonists (CCR5 antagonists)

These work by blocking a specific kind of "hook" on the outside of certain cells (CD4 cells)
so the virus can't plug in for replication.

Examples include

 Maraviroc or MVC (Selzentry) (only available member)

5.3 Post-Attachment Inhibitor or Monoclonal Antibody

This is a new class of antiviral medication specifically for adults living with HIV who have
tried multiple HIV medications and whose HIV has been resistant to current available
therapies. 

Ibalizumab-uiyk (Trogarzo), the only member of this class blocks your body’s HIV
infected cells from spreading the virus into those which are uninfected. It is administered
by IV.

This medication must be used with other antiretrovirals as part of an optimized

background therapy, or optimized background regimen.

6. gp120 Attachment Inhibitor

This is a new class of drug with currently just one medication, fostemsavir (Rukobia). It is
for adults who have tried multiple HIV medications and whose HIV has been resistant to
current available therapies. It targets the glycoprotein 120 on the surface of the virus,
stopping it from being able to attach itself to the CD4 T-cells of your body’s immune
system. 

OTHERS

Cytochrome P4503A (CYP3A) inhibitors

Cytochrome P4503A inhibitors, also known as CYP3A inhibitors, increase the levels of
certain HIV drugs (as well as other non-HIV drugs) in the body.

The following drugs are CYP3A inhibitors:

 Cobicistat (Tybost)- (doesn’t have the ability to promote anti-HIV activity when
it’s used alone)

 Ritonavir (Norvir)- (can promote anti-HIV activity when it’s used alone, must
be used in much higher doses than people can typically tolerate)

Pharmacologic enhancers, or "Drug Boosters"

These boost the effectiveness of certain HIV/AIDS medicines. A pharmacokinetic

enhancer slows the breakdown of the other medicine. This allows that medicine to stay
in the body longer at a higher concentration.

Ritonavir (RTV), taken in a low dose, increases blood levels of lopinavir (LPV) and the drug
LPV/r (Kaletra). 

Cobicistat (Tybost) does the same thing in combination

with atazanavir, darunavir, elvitegravir. 

 Atazanavir + cobicistat, or ATV/c (Evotaz)

 Darunavir + cobicistat, or DRV/c (Prezcobix)

 Elvitegravir + TDF + FTC + cobicistat, or EVG/c/TDF/FTC (Stribild)

 Elvitegravir + TAF + FTC + cobicistat, or EVG/c/TAF/FTC (Genvoya)

Note: "drug boosters" can increase the levels of other drugs and cause potential harm.

Combination drugs
Combination drugs combine multiple medications into one drug form. This type of
regimen is usually used to treat people who’ve never taken HIV medications before.

The following combination drugs only include a PI and a CYPA3A inhibitor:

 Atazanavir and cobicistat (Evotaz)

 Darunavir and cobicistat (Prezcobix)

 Lopinavir and ritonavir (Kaletra)

The CYPA3A inhibitor functions as a booster drug.

The following combination drugs only include NRTIs:

 Abacavir + lamivudine, or ABC/3TC (Epzicom)

 Abacavir + lamivudine + zidovudine, or ABC/3TC/ZDV (Trizivir)
 Tenofovir alafenamide + emtricitabine, or TAF/FTC (Descovy)
 Tenofovir disoproxil fumarate + emtricitabine, or TDF/FTC (Truvada)
 Tenofovir disoproxil fumarate + lamivudine, or TDF/3TC (Cimduo)
 Zidovudine + Lamivudine or ZDV/3TC (Combivir)

NOTE: Descovy and Truvada may also be prescribed to some people without HIV as
part of a pre-exposure prophylaxis (PrEP) regimen.

Multiclass combination drugs or single-tablet regimens (STRs)

The following combination drugs include both NRTIs and NNRTIs:

 Doravirine, lamivudine, and tenofovir disoproxil fumarate (Delstrigo)

 Efavirenz, lamivudine, and tenofovir disoproxil fumarate (Symfi)

 Efavirenz, lamivudine, and tenofovir disoproxil fumarate (Symfi Lo)

 Efavirenz + tenofovir disoproxil fumarate + emtricitabine, or

EFV/TDF/FTC (Atripla)

 Rilpivirine + tenofovir alafenamide + emtricitabine , or RPV/TAF/FTC (Odefsey)

 Rilpivirine + tenofovir disoproxil fumarate + emtricitabine or RPV/TDF/FTC

(Complera)
The following combination drugs include NRTIs, an INSTI, and the CYP3A
inhibitor cobicistat:

 Elvitegravir + cobicistat + tenofovir disoproxil fumarate + emtricitabine, or

EVG/c/TDF/FTC (Stribild)

 Elvitegravir + cobicistat +  tenofovir alafenamide + emtricitabine or

EVG/c/TAF/FTC (Genvoya)

The following combination drugs include at least one NRTI and an INSTI:

 Abacavir + Dolutegravir + lamivudine, or ABC/ DTG /3TC (Triumeq)

 Bictegravir + tenofovir alafenamide fumarate + emtricitabine, or BIC/TAF/FTC

(Biktarvy)

 Dolutegravir  + lamivudine, or DTG/3TC (Dovato)

The following combination drug includes an NNRTI and an INSTI:

 Dolutegravir + rilpivirine, or DTG/RPV (Juluca)

The following combination drug includes NRTIs, a PI, and the CYP3A inhibitor

cobicistat:

 Darunavir + cobicistat + tenofovir alafenamide + emtricitabine, or
DRV/c/TAF/FTC) (Symtuza)

HIV drug side effects

Many HIV drugs can cause temporary side effects when first used. In general, these
effects can include:

 Diarrhea  Nausea and Vomiting,

 Dizziness  Difficulty Sleeping,

 Headaches  Dry Mouth,

 Fatigue  Rash

 Fever  Pain