UNIT 5: ANTIVIRAL DRUGS
Key Unit Competence:
Utilize antiretroviral medications to limit HIV/AIDS transmission
Introductory activity 5.0
you.
5.1. Introduction to antiretroviral drugs
Learning Activity 5.1
During your clinical practice ,you receive a client in consultation. In data collection,
the client reports that he is taking antiretroviral drug.
1) What is an antiretroviral drug?
2) What is a protease inhibitor?
Guidance: Use internet and library textboks.
CONTENT SUMMARY
Antiviral: An agent that kills a virus or that suppresses its ability to replicate and,
hence, inhibits its capability to multiply and reproduce.
For example, amantadine (Symmetrel) is a synthetic antiviral. It acts by inhibiting the
multiplication of the influenzaA virus. It was used to lessen the severity of the disease,
particularly in individuals at high-risk such as those who are immunosuppressed or
in a nursing home.
The antivirals that have been developed are generally less effective than one
would like. Viruses can replicate rapidly and, in many cases sloppily, giving rise to
mutations that make them resistant to drugs. And for fast-moving viral infections
like flu or a cold, a drug must be very powerful to make a difference before the
disease runs its natural course.
Antivirals and Antiretrovirals are a class of medication specifically used to treat
viral and retroviral infections caused by viruses like HIV, herpes viruses, hepatitis
B and C. Antivirals are a class of drugs which are used to treat viral infections.
The antiviral drugs target diverse group of viruses such as herpes, hepatitis, and
influenza viruses. Whereas antiretroviral drugs are the drugs that are used to fight
retrovirus infections which mainly include HIV. Different classes of antiretroviral
drugs act on different stages of the HIV life cycle.
Retrovirus is a group of viruses that belong to the family Retroviridae and that
characteristically carry their genetic blueprint in the form of ribonucleic acid (RNA).
Retroviruses are named for an enzyme known as reverse transcriptase, which was
discovered independently in 1971 by American virologists Howard Temin and David
Baltimore. Reverse transcriptase transcribes RNA into deoxyribonucleic
acid (DNA), a process that constitutes a reversal of the usual direction of
cellular transcription (DNA into RNA). The action of reverse transcriptase makes it
possible for genetic material from a retrovirus to become permanently incorporated
into the DNA genome of an infected cell; the enzyme is widely used in the biological
sciences to synthesize genes.
Integrase inhibitor: a drug that inhibits the activity of the virus-specific enzyme
integrase, an encoded enzyme needed for viral replication; blocking this enzyme
prevents the formation of the HIV-1 provirus.
Interferon: tissue hormone that is released in response to viral invasion; blocks
viral replication nonnucleoside reverse transcriptase inhibitors: drugs that bind to
sites on the reverse transcriptase within the cell cytoplasm, preventing RNA- and
DNA-dependent DNA polymerase activities needed to carry out viral DNA synthesis;
prevents the transfer of information that allows the virus to replicate and survive.
Nucleoside reverse transcriptase inhibitors: drugs that prevent the growth of the
viral DNA chain, preventing it from inserting into the host DNA, so viral replicationcannot occur.
Protease inhibitors: drugs that block the activity of the enzyme protease in HIV;
protease is essential for the maturation of infectious virus, and its absence leads to
the formation of an immature and noninfective HIV particle.
CCR5 coreceptor antagonist: a drug that blocks the receptor site on the T cell
membrane that the HIV virus needs to interact with in order to enter the cell.
Fusion inhibitor: a drug that prevents the fusion of the HIV-1 virus with the human
cellular membrane, preventing it from entering the cell.
Self-assessment 5.1
1) which of the following is a definition of antiviral drugs?
a) Antivirals are a class of drugs which are used to treat viral infections
b) Antivirals are a class of drugs which are used to treat viral and bacterial
infections
c) Antivirals are a class of drugs which are used to treat retroviral infections
d) Antivirals are a class of drugs which are used to treat viral and retroviral
infections
2) You receive a client with signs and symptoms of helps simplex. Among
the two following groups of drugs, which one will you choose as effective
to the disease?
a) Antiretroviral drugs
b) Antiviral drugs
3) With an example of the virus infections. Differentiate antiviral and retroviraldrugs.
5.2. Classification of antiretroviral drugs
Learning Activity 5.2
You are an asociate nurse carrying out the clinical placement. You receive a
patient at the health facility who has been diagnosed with HIV/AIDS. What does
an associate nurse will tell the patient?
1) Which classes of antiretroviral drugs can be used in HIV/AIDS
management?2) What are the five basic goals of ART?
CONTENT SUMMARY
In this lesson we discuss on classification of antiretroviral drugs. HIV infection has
been transformed from a near-certain death sentence to a manageable chronic
disease. Because of viruses are contained inside human cells while they are in
the body, researchers have difficulty developing effective drugs that destroy a virus
without harming the human host. Since the introduction of ART, the incidence of
new opportunistic infections has declined dramatically. For example, the incidences
of cytomegalovirus retinitis and disseminated mycobacterial infection have fallen
by as much as 75% to 80%. In many patients with low CD4 T-cell counts, ART
has caused CD4 counts to rise, restoring some immunocompetence and permitting
withdrawal of prophylactic drugs.
Patients with HIV infection should receive ART regardless of the CD4 count or
phase of HIV disease. Treatment has five basic goals: Maximal and long-lasting
suppression of viral load, restoration and preservation of immune function, improved
quality of life, reduction of HIV-related morbidity and mortality and prevention of
HIV transmission. Most patients take several antiretroviral drugs typically two
nucleoside reverse transcriptase inhibitors (NRTIs) combined with either a PI or
non-nucleoside reverse transcriptase inhibitors (NNRTIs).
These highly effective regimens can reduce plasma HIV to undetectable levels,
causing CD4 T-cell counts to return toward normal, thereby restoring some immune
function. However, despite these advances, treatment cannot cure HIV. The HIV
mutates over time, presenting a slightly different configuration with each new
generation. Treatment of AIDS and ARC has been difficult for two reasons: (1)
the length of time the virus can remain dormant within the T cells (i.e., months to
years), and (2) the adverse effects of many potent drugs, which may include further
depression of the immune system. A combination of several different antiviral drugs
is used to attack the virus at various points in its life cycle to achieve maximum
effectiveness with the least amount of toxicity.
Antiretroviral drugs are classified into six classes of antiretroviral drugs. Four
classes: nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non nucleoside reverse transcriptase inhibitors (NNRTIs), integrase strand transfer
inhibitors (INSTIs), and protease inhibitors (PIs) inhibit HIV enzymes.
The other two classes: HIV fusion inhibitors and CCR5 antagonists, work outside
CD4 cells to block HIV entry.
NRTIs suppress HIV replication in two ways: (1) they become incorporated into
the growing strand of viral DNA (through the actions of reverse transcriptase) and
thereby prevent further strand growth, and (2) they compete with natural nucleoside
triphosphates for binding to the active center of reverse transcriptase and thereby
competitively inhibit the enzyme. To interact with reverse transcriptase, NRTIs mustfirst undergo intracellular conversion to their active (triphosphate) forms.
The NNRTIs differ from the NRTIs in structure and mechanism of action. As
their name suggests, the NNRTIs have no structural relationship with naturally
occurring nucleosides. Also unlike NRTIs, the NNRTIs are active only against HIV1. In practice, they are usually combined with an NRTI. The NNRTIs bind to the
active center of reverse transcriptase enzyme. At this location, the NNRTI causes
stereochemical changes (i.e., changes in the spatial arrangement of atoms forming
the structure of molecules). This hampers the ability of nucleosides to bind, which
inhibits DNA replication and promotes premature termination of the growing DNA
strand.
NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs)
The NRTIs were the first drugs used against HIV infection. As their name suggests,
the NRTIs are chemical relatives of naturally occurring nucleosides or nucleotides,
the building blocks of DNA. At this time, seven NRTIs are available: Abacavir,
didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine. The
NRTIs are effective against both HIV-1 and HIV-2; however, their activity is greater
for HIV-1. The NRTIs are ineffective as monotherapy because resistance develops
rapidly. First-line antiretroviral regimens include two NRTIs and one other drug. The
availability of combination antiretroviral products has simplified treatment.
Mechanism of Action
All NRTIs are prodrugs that inhibit HIV replication by suppressing synthesis
of viral DNA. To do this, they must first undergo intracellular conversion to their
active (phosphate) form. In their active form, they act as substrates for reverse
transcriptase. However, after they become incorporated into the growing DNA
strand, they prevent reverse transcriptase from adding more bases. As a result, all
further growth of the DNA strand is blocked. In addition to causing premature strand
termination, the activated NRTI competes with natural nucleoside triphosphates for
binding to the active site of reverse transcriptase.
Adverse Effects
The NRTIs share a core of adverse effects associated with mitochondrial toxicity.
Recall that mitochondria are cellular organelles that take in nutrients and convert
them into ATP for energy. NRTIs can disrupt synthesis of mitochondrial DNA and
can thereby impair mitochondrial function.
The main adverse effects of NRTIs are: Lactic acidosis, hepatic steatosis. Other
adverse effects include: pancreatitis and myopathies, which are likely tied to lactic
acidosis. Adverse effects of individual NRTIs are discussed separately.
Drug Interactions
NRTIs have fewer drug interactions than most antiretroviral drugs, in part because
most are not metabolized by the P450 enzymes. Interactions of individual drugs arediscussed separately.
Table 5.1.1: NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs)
NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
The NNRTIs differ from the NRTIs in structure and mechanism of action. As their
name suggests, the NNRTIs have no structural relationship with naturally occurring
nucleosides. Also unlike NRTIs, the NNRTIs are active only against HIV-1. In
practice, they are usually combined with an NRTI. At this time, five NNRTIs are
available: efavirenz (Sustiva), nevirapine (Viramune), Delavirdine (Rescriptor),etravirine (Intelence), and rilpivirine (Edurant).
Mechanism of Action
In contrast to the NRTIs, the NNRTIs bind to the active center of reverse transcriptase
enzyme. At this location, the NNRTI causes stereochemical changes (i.e., changes
in the spatial arrangement of atoms forming the structure of molecules). This
hampers the ability of nucleosides to bind, which inhibits DNA replication and
promotes premature termination of the growing DNA strand.
Adverse Effects
Unlike NRTIs, there are no adverse effects shared by all NNRTIs. However, two of
the NNRTIs, efavirenz and rilpivirine, can both cause CNS effects.
Drug Interactions
The NNRTIs have multiple drug interactions with commonly used drugs across
many drug classes. These vary according to the individual NNRTI in question.Table 5.1.2: NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
PROTEASE INHIBITORS
PIs are active against both HIV-1 and HIV-2. They are among the most effective
antiretroviral drugs available. When used in combination with NRTIs, they can
reduce viral load to a level that is undetectable with current assays.
As with other antiretroviral drugs, HIV resistance can be a significant problem.
Mutant strains of HIV that are resistant to one PI are likely to be cross-resistant
to other PIs. In contrast, since PIs do not share the same mechanism as other
antiretroviral drugs, cross-resistance between PIs and these drugs does not occur.
To reduce the risk for resistance, PIs should never be used alone; rather, they
should always be combined with at least one reverse transcriptase inhibitor, and
preferably two.
Nine PIs are available: atazanavir, darunavir, fosamprenavir, indinavir, lopinavir
(with ritonavir), nelfinavir, ritonavir, saquinavir, and tipranavir.
Mechanism of Action
Maturation is necessary for HIV to infect CD4 cells; immature forms are noninfectious.
Protease inhibitors prevent HIV maturation by blocking the HIV enzyme protease. It
may help to look at the process of HIV maturation.
When the various enzymes and structural proteins of HIV are synthesized, they
are not produced as separate entities; rather, they are strung together in large
polyproteins. Protease catalyzes the cleavage of bonds in the polyproteins, thereby
freeing the individual enzymes and structural proteins. Once these components
have been freed, HIV uses them to complete its maturation. Protease inhibitors
bind to the active site of HIV protease and prevent the enzyme from cleaving HIV
polyproteins. As a result, the structural proteins and enzymes of HIV are unable to
function, and hence the virus remains immature and non-infectious.
Adverse Effects
There are several adverse effects that all protease inhibitors have in common.
These include hyperglycemia and the development of diabetes, lipodystrophy
(fat redistribution), elevation of serum transaminases, and decreased cardiac
conduction velocity. They can also increase bleeding in patients with hemophilia.
Drug Interactions
All PIs are metabolized by cytochrome P450 enzymes, and all PIs can inhibit
selected cytochrome P450 enzymes. Typically, they will also induce other enzymes.
As a result, PIs can interact with drugs that inhibit or induce P450 enzymes and
with drugs that are substrates for P450 enzymes. Not all interactions are harmful, of
course. By inhibiting selected P450 enzymes one PI can increase the level of anotherPI and can thus intensify therapeutic effects. One PI—ritonavir [Norvir]—is routinely
combined with other PIs with the specific purpose of increasing the therapeutic
effects of the other PI. In this technique, known as ritonavir boosting, the dose of
ritonavir is low: 100 to 400 mg/day. This dosage is too low to contribute significant
antiviral effects, but still high enough to inhibit P450 metabolism. Unfortunately,
most interactions with PIs are not beneficial. We will highlight interactions commonlyexperienced by patients with HIV in our discussion of individual PIs.
Table 5.1.3: PROTEASE INHIBITORS
INTEGRASE STRAND TRANSFER INHIBITORS
HIV integrase strand transfer inhibitors (INSTIs), or simply integrase inhibitors,
target HIV by terminating the integration of HIV into DNA. Integrase is one of three
viral enzymes needed for HIV replication. As its name implies, integrase inserts
HIV genetic material into the DNA of CD4 cells. By inhibiting integrase, these drugs
prevent insertion of HIV DNA and thereby stop HIV replication. They are effective
against both HIV-1 and HIV-2.
We currently have three approved INSTIs: raltegravir, dolutegravir, and elvitegravir.
All are indicated for combined use with other antiretroviral agents to treat adults
infected with HIV-1.
Actions and Use
Raltegravir [Isentress] was the first HIV integrase strand transfer inhibitor to be
developed. Raltegravir stops HIV replication by preventing insertion of HIV DNA.
Raltegravir is active against HIV strains resistant to some of the other drugs.
Raltegravir was originally approved only for treatmentexperienced patients but is
now approved for treatment-naïve patients as well. In current guidelines, raltegravir
(in combination with tenofovir plus either emtricitabine or lamivudine) is considered
a first-choice drug for HIV treatment. In clinical trials, raltegravir demonstrated
increased viral suppression when compared to protease inhibitors and the NNRTI
efavirenz. Unfortunately, HIV resistance was also more likely to develop.
Adverse Effects
Raltegravir is generally well tolerated by most. The most common adverse effect
is an elevation in liver enzymes that occurs in about 10% of those taking the
drug. Approximately 4% to 5% will have elevations in serum amylase and lipase.
Symptomatic adverse effects occur infrequently. In fact, the most common adverse
effects, insomnia and headache, occur in only 2% to 4% of those taking this drug.
In clinical trials, a few patients experienced myopathy and rhabdomyolysis, but
a causal relationship has not been established. Rarely, patients have developed
severe hypersensitivity reactions. Skin reactions include Stevens-Johnson
syndrome and toxic epidermal necrolysis, which can be fatal. Organ dysfunction,
including liver failure, may also develop.
Patients who develop signs of a hypersensitivity reaction (e.g., severe rash, or rash
associated with blisters, fever, malaise, fatigue, oral lesions, facial edema, hepatitis,
angioedema, muscle or joint aches) should discontinue raltegravir immediately.
Contraindications
There are no contraindications to taking raltegravir. Those with pre-existing hepatic
impairment may be at risk for worsening of this condition. Caution should be
maintained when taken by patients with a history of rhabdomyolysis or by those
taking other drugs that have this adverse effect.
Drug Interactions
Because raltegravir is metabolized by glucuronidation, it does not have as many
drug interactions as those with roles in P450 enzyme systems. Atazanavir and other
inhibitors of UGT can increase levels of raltegravir. Conversely, inducers of UGT
(e.g., efavirenz, fosamprenavir, rifabutin, tipranavir) can lower raltegravir levels.
HIV FUSION INHIBITORS
Unlike most other drugs for HIV, which inhibit essential viral enzymes (i.e., reverse
transcriptase, integrase, protease), HIV fusion inhibitors block entry of HIV into
CD4 T cells. Earlier in the chapter, we discussed the replication cycle of HIV. Recall
that in step 2, the lipid bilayer envelope of HIV fuses with the lipid bilayer of the host
cell membrane. HIV fusion inhibitors block this fusion process.
Enfuvirtide
Enfuvirtide [Fuzeon], widely known as T-20, is the first and only HIV fusion inhibitor
currently approved by the FDA. Unfortunately, although enfuvirtide is effective,
it is also inconvenient (treatment requires twice-daily subQ injections) and very
expensive (treatment costs about $52,000 a year). Furthermore, injection-site
reactions occur in nearly all patients.
Mechanism of Action
Enfuvirtide prevents the HIV envelope from fusing with the cell membrane of CD4
cells, and thereby blocks viral entry and replication. Fusion inhibition results from
binding of enfuvirtide to gp41, a subunit of the glycoproteins embedded in the
HIV envelope (see Fig. 94.1). As a result of enfuvirtide binding, the glycoprotein
becomes rigid, and hence cannot undergo the configurational change needed to
permit fusion of HIV with the cell membrane.
Resistance
Resistance to enfuvirtide has developed in cultured cells and in patients. The cause
is a structural change in gp41. In clinical trials, reductions in drug susceptibility have
ranged from 4- to 422-fold. Fortunately, the HIV mutations that confer resistance to
enfuvirtide do not confer cross-resistance to NRTIs, NNRTIs, PIs, INSTIs, or CCR5
antagonists. Conversely, resistance to NRTIs, NNRTIs, PIs, INSTIs, or CCR5
antagonists does not confer cross-resistance to enfuvirtide. The rate at which
resistance develops depends on the efficacy of the drugs used concurrently. When
the patient’s other antiretroviral drugs are still effective, resistance to enfuvirtide
develops relatively slowly. However, when there is significant resistance to the
other drugs, resistance to enfuvirtide develops rapidly.
Therapeutic use
Use Enfuvirtide is reserved for treating HIV-1 infection that has become resistant
to other antiretroviral agents. Specifically, the drug is indicated for HIV-1 infection
in patients who are treatment experienced and have evidence of HIV replication
despite ongoing ART. To delay emergence of resistance, enfuvirtide should always
be combined with other antiretroviral drugs.
Adverse Effects
They include injection-site reactions, pneumonia, and hypersensitivity
reactions.
Drug Interactions
Enfuvirtide appears devoid of significant drug interactions. There are no interactions
with other antiretroviral drugs that would require a dosage adjustment for either
enfuvirtide or the other agent.
Table 5.1.4: INTEGRASE INHIBITORS
CCR5 ANTAGONISTS
CCR5 antagonists, like the fusion inhibitors, block entry of HIV into CD4 T cells.
However, the mechanism by which they accomplish this is different.
Maraviroc
Maraviroc [Selzentry, Celsentri ] is the first, and currently only, representative of
the CCR5 antagonists. Maraviroc isn’t usually used for initial treatment of HIV. It
appears most effective in treating patients with drug-resistant HIV.
Mechanism of Action
CCR5 is a co-receptor that some strains of HIV must bind with to enter CD4 cells.
Maraviroc binds with CCR5 and thereby blocks viral entry. HIV strains that require
CCR5 for entry are referred to as being CCR5 tropic. Between 50% and 60%
of patients are infected with this type of HIV. Maraviroc and enfuvirtide (a fusion
inhibitor) are the only antiretroviral drugs that block HIV entry.
Therapeutic Use
Maraviroc is indicated for combined use with other antiretroviral agents to treat
patients age 16 years and older who are infected with CCR5-tropic HIV-1 strains.
The drug was originally approved only for treatment-experienced patients but is
now approved for treatment-naïve patients as well. Before maraviroc is used, a test
must be performed to confirm that the infecting HIV strain is CCR5 tropic.
Adverse Effects
The most common side effects are cough, dizziness, pyrexia, rash, abdominal
pain, musculoskeletal symptoms, and upper respiratory tract infections. Intensity is
generally mild to moderate. Liver injury has been seen in some patients and may be
preceded by signs of an allergic reaction (e.g., eosinophilia, pruritic rash, elevated
immunoglobulin E).
Patients should be informed about signs of an evolving reaction (itchy rash, jaundice,
vomiting, and/or abdominal pain) and instructed to stop maraviroc and seek medical
attention. During clinical trials, a few patients experienced cardiovascular events,
including myocardial ischemia and MI. Maraviroc should be used with caution in
patients with cardiovascular risk factors.
Drug Interactions
Because maraviroc is metabolized by CYP3A4, drugs that inhibit or induce this
enzyme will affect maraviroc levels. Levels will be raised by strong CYP3A4
inhibitors, including protease inhibitors (except tipranavir/ritonavir) and delavirdine.
Conversely, maraviroc levels will be lowered by strong CYP3A4 inducers, including
etravirine and efavirenz. As always, it is important to check for interactions via acomprehensive database before administering drugs such as this one.
Table 5.1.5: FUSIOIN INHIBITORS
Self-assessment 5.2
1) Why is combination therapy necessary in HIV treatment?
2) Which of the following antiretroviral drugs is classified in the protease
inhibitors?
a) Enfuvirtide
b) Raltegravir
c) Atazanavir
d) Nevirapine3) What is the mechanism of action of enfuvirtide?
5.3. Antiretroviral treatment in adolescents and adults
Learning Activity 5.3
A 33-year-old newly diagnosed HIV patient was advised to start antiretroviral
treatment at ART sevice where you are appointed as an associate nurse. During
pre-treatment counselling, you focus on the number of combined medications
to use.
1) What is the number of medications combinations is required to use in
HIV/AIDS management?
2) What should the nurse include in the teaching as the ideal time to initiateARVs after HIV diagnosis?
CONTENT SUMMARY
People with HIV should take medicine to treat HIV as soon as possible. HIV
medicine reduces the amount of HIV in the body (viral load) to a very low level,
which keeps the immune system working and prevents illness. It can even make
the viral load so low that a test can’t detect it. This is called an undetectable viral
load. Getting and keeping an undetectable viral load* is the best thing people with
HIV can do to stay healthy.
Initiating Antiretroviral Therapy: ART regimens typically contain at least three
drugs. Regimens that contain only two drugs are not generally recommended,
and monotherapy should always be avoided, except possibly during pregnancy.
Additionally, all ART regimens contain drugs from at least two different classes.
By using drugs from different classes, we can attack HIV in two different ways
(e.g., inhibition of reverse transcriptase and inhibition of protease) and can thereby
enhance antiviral effects.
Criteria for Eligibility to ART in Adults and adolescent: Antiretroviral therapy
(ART) is recommended for all persons with HIV to reduce morbidity and mortality
and to prevent the transmission of HIV to others. The Panel on Antiretroviral
Guidelines for Adults and Adolescents recommends initiating ART immediately (or
as soon as possible) after HIV diagnosis in order to increase the uptake of ART and
linkage to care, decrease the time to viral suppression for individual patients, and
improve the rate of virologic suppression among persons with HIV.
In addition to enhancing antiviral effects, the use of multiple drugs reduces the risk
for resistance. Resistance reduction occurs because the probability that HIV will
undergo a mutation that confers simultaneous resistance to three or four drugs is
much smaller than the probability of undergoing a mutation that confers resistance
to just one drug.
Below are key considerations in clinical management of adolescents and adults
living with HIV:
• Clinical and laboratory evaluations are the cornerstones of care and treatment
of HIV positive adolescents and adults.
• Renal creatinine clearance is mandatory for adolescents and adults since
they initiate with TDF based regimen.
• Viral load monitoring should be conducted at 6 months and at 12 months
after ART initiation, and annually thereafter. DTG-based regimen remains the
preferred first-line option.
• TDF/3TC/EFV600mg is the alternative first-line regimen for adults and
adolescents who cannot take TLD
• DTG-based regimen is the preferred 2nd line option for patients failing a non DTG 1st line regimen.
• For patients failing DTG-based regimen, specialist consultation and
genotyping should be considered.
• PLHIV with advanced HIV disease should be offered a package of interventions
including screening, treatment and/or prophylaxis for major OIs, rapid ART
initiation and intensified adherence support.
• TB screening should be done at enrolment and at each clinical visit
• Cotrimoxazole should be given to patients with advanced diseases.
Clinical evaluation
• Present and past medical history
• Comprehensive physical examination
• WHO staging
• Drug history
• Sexual history
• Nutrition status assessment
• OI screening (e.g. TB)
• NCDs screening mainly (Refer annex V).
• Cardiovascular disease: blood pressure, cardiomyopathies
• Malignancies: cervical cancer, breast cancer
• Metabolic diseases: diabetes, hyperlipidemia, hypocholesteremia
• Mental health illness
Laboratory evaluation Baseline:
• CD4 cell count,
• Cryptococcus antigen (if CD4 count < 200 cells/mm3)
• Renal function (creatinine and calculation of creatinine clearance)
• Hepatitis B surface antigen (Ag HBs)
• Hepatitis C antibody (HCV Ab)
• LFTs
• GeneXpert if TB screening is positive
• Additional investigations as clinically indicate
ART Regimen in adolescents and Adult
First line ART regimen options
There are two options recommended in first line regimen
DTG-based
NNRTI-based
Dosage and administration of first-line regimenDosage and administration of first-line regimen
1) TDF/3TC/DTG (300/300/50 mg) (OD)
2) ABC/3TC (600/300 mg) + DTG (50 mg) (OD)
3) TDF/3TC/EFV (300/300/400mg)
4) ABC/3TC (600/300mg) + EFV 600mg
Notes:
• Encourage taking EFV based regimens in the evening before 8:00 pm to
minimize dizziness
• Patients with EFV associated side effects should be advised to take it either
1-2 hours before or after meals to minimize side effects
Management of treatment failure among adolescents and adults
The monitoring of ART response and identification of treatment failure are the same
as for children
• For early management of treatment failure as well as second line treatment
failure refer to the treatment failure algorithm in children section.
Recommended regimens for second-line ART
Recommended regimens for 2nd line ART in adults after failure of specific first lineregimens.
In case of hepatitis B co-infection, maintain TDF: TDF+AZT/3TC+ATC/r or LPV/r
Recommended regimens for third-line
• DTG 50mg BID + Darunavir/ritonavir + Optimized NRTI or Etravirine can be
used based on genotyping results
• The 3rd line regimen must only be given upon expert consultation and usually
with the assistance of genotyping results.• Before prescribing third-line therapy, the patient must undergo extensive
additional adherence counselling and should have a treatment partner
involved in adherence assistance. Adherence counselling is critical to the
success of this regimen.
• NRTI backbone may be necessary based on genotyping test or in case of
Hepatitis B co-infection
Monitoring of adolescents and adults on ART
Clinical evaluation and laboratory tests play a key role in assessing adolescents
and adults before ART initiation, and then monitoring their treatment response as
well as possible toxicity of antiretrovirals. Note that once started, ART is a treatment
for life but should be changed in the following cases:
• Drug toxicity
• Drug-drug interactions
• Co-infection
• Treatment failure confirmed by viral load
Notes:
• The follow up of CD4 count should be done whenever clinically indicated.
• For STIs management, refer to national guidelines for STIs and hepatitis.
1) TREATMENT FAILURE
Treatment failure is arguably the most compelling reason for changing the regimen.
Failure is indicated if:
• Plasma HIV RNA remains above 200 copies/mL after 24 weeks
• Plasma HIV RNA remains above 50 copies/mL after 48 weeks
• Plasma HIV RNA rebounds after falling to an undetectable level
• CD4 T-cell counts continue to drop despite antiretroviral treatment
• Clinical disease progresses despite antiretroviral treatment
2) DRUG TOXICITY
If a patient experiences toxicity typical of a particular drug in the regimen, that drug
should be withdrawn and replaced with a drug that is (1) from the same class and
(2) of equal efficacy. For example, if a patient taking zidovudine were to develop
anemia and neutropenia, zidovudine should be discontinued and replaced with
another NRTI (e.g., stavudine). Note that when toxicity is the reason for altering the
regimen, changing just one drug is proper, whereas when resistance or suboptimal
treatment is the reason, at least two of the drugs should be changed.
3) Promoting Patient Adherence
To achieve treatment goals and delay emergence of resistance, strict adherence
to the prescribed regimen is critical. Unfortunately, several factors: duration oftreatment, complex medication regimens, multiple adverse drug effects, drug-drug
interactions, and drug-food interactions make adherence to ART challenging for
patients.
The factors that predict poor adherence (e.g., poor clinician-patient relationship,
active use of alcohol or street drugs, depression and other mental illnesses), as well
as factors that predict good adherence (e.g., availability of emotional and practical
support, ability to fit dosing into the daily routine, appreciation that poor adherencewill cause treatment failure).
Self-assessment 5.3
1) What is the preferred 1st line regimen for adolescents and adults?
2) What is the alternative first-line regimen for adults and adolescents who
cannot take TLD?
3) What can be done if a patient experiences toxicity typical of a particulardrug in the regimen?
5.4. Antiretroviral treatment in Children
Learning Activity 5.4
You are an associate nurse and you receive a mother bringing her 2-year-old baby
who was born with HIV. She wants the baby to be started on antiretroviral drugs,
and there is a student in the clinical placement who doubts on the antiretroviral
drugs to administer to the baby.
1) Which regimen should the baby start with?
2) The symptoms of HIV infection generally start later compared to the time
it takes for adults to develop symptoms. TRUE or FALSE
3) The preferred 1st line ART option for children of 30kgs and above isABC/3TC+LPV/r. TRUE or FALSE
CONTENT SUMMARY
In young children, the course of HIV infection is accelerated. Whereas adults
generally remain symptom free for a decade or more, many children develop
symptoms by their first birthday. Death often ensues by age 5 even with ART. Why
do young children succumb so quickly?
Primarily because their immune systems are immature, and hence less able to fend
off the virus. Because immune function is limited, levels of HIV RNA climb higher in
toddlers than in adults, and then decline at a much slower rate.In very young patients, diagnosis and monitoring of HIV infection employs different
methods than those used in adolescents and adults. In particular, for infants under
18 months of age, diagnosis should be based on viral load assays, not on antibody
tests. For children under 5 years of age, monitoring of immune status should be
based on the percentage of CD4 cells, not on absolute CD4 counts.
Like older patients, young patients should be treated with a combination of
antiretroviral drugs, with the goals of (1) reducing plasma viral HIV to an undetectable
level and (2) stabilizing or improving immune status.
Clinical and laboratory evaluations are the cornerstones of care and treatment of
HIV positive children of ≤10 years old. DTG is used for children with weight ≥ 20kgs.
The preferred 1st line option for children less than 20kg is ABC/3TC+LPV/r. The
preferred 1st line option for children of ≥ 20kg ABC/3TC+DTG. The preferred 1st
line option for children of 30kgs and above without renal failure is TDF/3TC/DTG.
For children on LPV/r, the preferred formulation is pellet (40mg/10mg, oral pellet)
due to its storage and palatability reasons.
For children with more than 15kg, ATV/r can be used to replace LPV/r. For children
on ABC/3TC, 120/60mg is the preferred strength. ABC is contra-indicated for
children less than 3 months. If HIV is confirmed before 3 months, the recommended
1st line ART regimen is AZT+3TC+LPV/r. Switch to AZT-based regimen in case
of intolerance to ABC. LPV/r is contra-indicated for new-born less than 15 days.
If switching from AZT-based regimen, consider VL (viral load) suppression. If
treatment failure, consider second line regimen.
TB screening is mandatory for all children at enrolment and at each clinical visit.
TPT (Tuberculosis preventive therapy) should be integrated in HIV management.
IPT (Isoniazid preventive therapy: Isoniazid 10mg/Kg) is used for 6 Months to all
HIV children of ≤5 years old without active TB but with a history of TB contact. Anti TB should be initiated immediately and ART within 2 to 8 weeks. The treatment
failure (TF) is defined by the virological failure (plasma viral load >1000 copies/ml)
based on two consecutive viral load measurements after 3 months with intensive
adherence support. The management of 1st line TF is done after identifying its
probable cause and then act as shown by figure 7. The recognition of 2nd line TF
is similar to the 1st line TF and the shift to 3rd line is guided by genotyping and
expert consultation. The monitoring of children on ART encompasses clinical and
laboratory monitoring in order to assess treatment response and potential drugtoxicity.
ART Regimen for children younger than 10 years of ageTable 5.4.1 First line options for ART regimen in children:
Table 5.1.2: Initiation of ART in children
Table 5.1.3:Children who are already on ART
Second-line ART in Children
Self-assessment 5.4
1) When the HIV positive children should be screened for TB infection?
2) Which ART regimen should a 9-year-old child be started with?
3) Which of the following options is true with regard to treatment of patients
with HIV and TB coinfection?
a) ART should be initiated immediately and anti-TB within 2 to 8 weeks
b) Anti-TB should be initiated immediately and ART within 2 to 8 weeks
c) ART should be initiated immediately and anti-TB within 6 weeksd) Anti-TB should be initiated immediately and ART within 12 weeks
5.5. ARV Treatment in Pregnant Women
Learning Activity 5.5
A woman of 25 years of age was diagnosed for HIV positive during antenatal
care at the health center. According to WHO/CDC, it is recommended that all
HIV positive women should take ARTs.
Read the pharmacology book and respond the following questions
1) When a pregnant woman newly diagnosed HIV positive should start the
treatment?2) What is the ART regimen for an HIV positive pregnant woman?
CONTENT SUMMARY
In general, the management of HIV infection in pregnant women should follow the
same guidelines for managing HIV infection in nonpregnant adults. Accordingly,
current guidelines recommend ART for all pregnant HIV-infected women. ART is
needed not only for maternal health, but also to reduce the risk for perinatal HIV
transmission.
Drug selection is challenging in that information on pharmacokinetics and safety
during pregnancy is limited.
When treating HIV infection in pregnant women, the goal is to balance the benefits
of treatment, reducing viral load, thereby promoting the health of the mother and
decreasing the risk for vertical HIV transmission (i.e., transmission to the foetus)
against the risks of drug-induced fetal harm (e.g., teratogenesis, lactic acidosis,
death). As a rule, the benefits of treatment outweigh the risks.
The primary determinants of therapy are the clinical, virologic, and immunologic
status of the mother; pregnancy is a secondary consideration. Nonetheless,
pregnancy should not be ignored.
Routine HIV testing for all pregnant women attending ANC for first time during
current pregnancy together with their male partners (unless already known HIV
positive status). It is preferable that these services are offered during the first
trimester of pregnancy but they should be ongoing until delivery.
Every HIV-positive woman will be provided with specific counselling on family
planning and get an access to a family planning method of her choice.
HIV positive pregnant and breastfeeding women should be offered index testing,partner notification and family testing services.
Every pregnant woman whose HIV status is unknown during ANC should be tested
for HIV at the time of delivery.
Every pregnant woman who tested HIV negative during ANC should be retested at
the time of delivery. Thereafter, retesting during postnatal period will be based on
HIV risk assessment outcomes.
Women tested HIV positive during ANC or at the time of labor, should start anti retroviral therapy immediately. In case of delay, ART initiation should not go beyond
7days.
Every pregnant or breastfeeding woman newly tested positive for HIV should start
with ART regimen Tenofovir + Lamivudine + Dolutegravir.
Every pregnant or breastfeeding woman newly tested HIV-positive and on ART,
should receive the first viral load test three months after ART initiation and then
after every six months until the end of PMTCT follow up.
All infants born to a known HIV positive mother should receive ART prophylaxis
with zidovudine and Nevirapine immediately. If not done immediately, it should be
in first 72 hours post-partum or as soon as possible during the first six weeks of life.
All HIV exposed or infected children should have regular growth monitoring to enable
early detection of growth retardation and undertake appropriate management.
Pre exposure prophylaxis is offered in the context of PMTCT to HIV negative
pregnant and/or breastfeeding women in the following circumstances:
• Women in discordant relationship whose partners are either not on ART or
are on ART but not virally suppressed
• Women practicing sex work
The regimen recommended for PrEP is a once daily TRUVADA or Tenofovir and
Lamivudine for the entire pregnancy and breastfeeding period.
The use of ART for HIV positive pregnant women will depend on whether she was
already on ART or not. The following situations are possible during pregnancy:
c) If the HIV-Positive pregnant woman is already initiated on ART,
consider the following aspects:
• Adherence to the current ART regimen
• Viral load suppression as per the most recent viral load test results
• Consider viral load result as ‘recent’ if it was performed less than six months
prior to the first ANC visit.
• It is mandatory to repeat the viral load test for all pregnant women not tested
at the first ANC, before the third term of pregnancy (preferably at 6 months of
pregnancy)
• If the woman is virally suppressed, she will be kept on her current ARTregimen
• If the woman is not virally suppressed (>200 copies/ml), she will be switched
to a Dolutegravir based regimen plus two NRTIs.
• The switch to Dolutegravir- based regimen will be conducted concurrently with
the adherence counselling for patients with documented poor adherence.
d) If a woman is newly diagnosed HIV positive during pregnancy:
• The woman is immediately enrolled in care and initiated on ART
• The preferred ART regimen is Tenofovir + Lamivudine + Dolutegravir
(TDF+3TC+DTG)
• Any woman with impaired renal function or any contraindication to TDF will
receive ABC + 3TC+DTG
NOTE: Doses are the same as in non-pregnant adults’ HIV treatment.Monitoring of renal function is important.
NOTE: Doses are the same as in non-pregnant adults’ HIV treatment.Monitoring of renal function is important.
Self-assessment 5.5
1) Any pregnant woman whose HIV status is unknown during ANC doesn’t
need to be tested for HIV at the time of delivery. TRUE or FALSE
2) Given their fragile status, the pregnant women with HIV positive status
should benefit from lower doses of ARTs compared to the non-pregnant
adults. TRUE or FALSE
3) Which of the following treatment regimens is used as ART initiation among
pregnant women in Rwanda?
a) Abacavir + Lamivudine + Dolutegravir.
b) Tenofovir + Lamivudine + Dolutegravir.
c) Efavirenz + Lamivudine + Dolutegravir.d) Nevirapine + Lamivudine + Dolutegravir.
5.6. Prophylaxis in new-borns with Perinatal HIV Exposureor HIV Infection
Learning Activity 5.6
Visit library and read pharmacology books /use internet and respond to following
question:
When should the newborn exposed perinatally to HIV start taking newborn ARVregimens?
CONTENT SUMMARY
A child is considered as ‘exposed to HIV’, if he/she is born to an HIV positive mother.
The initiation of infant prophylaxis depends on the time the mother was diagnosed
HIV positive. Children born to HIV negative mothers in discordant couple will not
receive any prophylaxis as long as their mothers remain HIV negative.
Infant born to a known HIV-positive mother:
All children born to a known HIV positive mother (before or during labour) will receive
zidovudine and Nevirapine (AZT+ NVP) as soon as possible within 72 hours after
birth up to six weeks of life. The baby will also start cotrimoxazole prophylaxis at
the age of 6 weeks until the final confirmation of HIV negative status at the age of
24 months.
Infant born to a mother diagnosed for HIV after delivery
If the mother is identified to be HIV-positive at the time of breastfeeding, she should
be put on ART. The child will start a combined AZT and NVP as soon as possible
for six weeks. At the end of 6 weeks ART prophylaxis; the child will also start
cotrimoxazole prophylaxis until the final confirmation of HIV negative status at 24
months of life.
All Breastfed infants who are at high risk of acquiring HIV, including those first
identified as exposed to HIV during the postpartum period, should continue infant
prophylaxis for an additional 6 weeks (total of 12 weeks of infant prophylaxis) using
NVP and AZT.
High-risk infants are defined as:
Infant born to women with established HIV infection who have received less than
four weeks of ART at the time of delivery; or born to women with established HIV
infection with viral load >1000 copies/mL in the four weeks before delivery, if viral
load measurement available; OR identified for the first time during the postpartumperiod, with or without a negative HIV test prenatally.
Self-assessment 5.6
1) During clinical practice in maternity ward, you receive a woman with
baby at the second day of home delivery. You take blood sample for HIV
testing. After 3 hours you receive a laboratory technician’ s call informing
you that the mother is HIV positive. Explain the management of motherand her baby to prevent mother to child transmission.
5.7. HIV Prevention among Discordant Couples
Learning Activity 5.7
1) A couple consults the healthcare facility where you are carrying out the
clinical placement, and they report they are discordant. The senior nurse
tasks you to explain to the couple the overall interventions package for
that discordant couple. What is that package?2) What are the objectives of these interventions?
CONTENT SUMMARY
Evidence-based interventions package for HIV sero-discordant couples can
be provided through facility based and/or community interventions. Although
these interventions are delivered in a package, providers must ensure that they
contextualize the specific, particular needs of the couple since different couples
may have different needs.
The objectives of these interventions are:
• To protect the negative partners from acquiring HIV infection
• To provide care and treatment to HIV positive partners, allowing them access
to early treatment that improves clinical outcomes
• To protect future children from HIV infections
• To offer the appropriate HIV prevention package for children and other family
members of the HIV positive individuals
• To support the prevention of unwanted pregnancies in discordant couples
The overall intervention package for discordant couples consists of the
following:
• Risk reduction counselling and condom provision
• Initiation of pre-exposure prophylaxis for those whose HIV positive partner is
not yet on ARV or are not virally suppressed
• Family planning counselling and service provision
• Repeat HIV testing for the uninfected partner every 12 months
• Care and treatment for the HIV-positive partner
• STI screening and treatment
In case of a pregnant HIV-negative partner:
• The HIV testing shall be done every three months
• A pre-exposure prophylaxis should be offered in case of non-viral suppression
for the positive partner.
• At labor a single dose of TDF+3TC+DTG will be offered for all women whoare not taking the pre-exposure prophylaxis.
The health care provider should encourage the discordant couple to follow up in
the same health facility and synchronize with pharmacy refills and appointment
schedule. Ongoing psychosocial support and counselling shall be offered to thediscordant couple.
Self-assessment 5.7
1) The health care provider should encourage the discordant couple to
follow up in the same health facility and synchronize with pharmacy refills
and appointment schedule. TRUE or FALSE
2) Pregnant HIV-negative partner in discordant couples should receive asingle dose of TDF+3TC+DTG at labor if they are not taking the pre exposure prophylaxis. TRUE or FALSE
5.8. ART for Post-Exposure Prophylaxis (PEP)
Learning Activity 5.8
3) While he was giving IM injection to a known HIV positive patient, an
associate nurse injured himself with a needle after injecting the drug. The
senior nurse sends him to the ART service for post exposure prophylaxis.
Which drugs may preferably be administered to this patient?
4) An HIV serology test should be performed for the exposed caregiver as
soon as possible (ideally within 72 hours). TRUE or FALSE
CONTENT SUMMARY
Every person who has experienced exposure to blood/body fluids, victim of sexual
assault, or accidental sexual exposure
(i.e., condomless, sex with a known HIV positive person; condom breakage) must have access to an early evaluation of the risk of HIV infection and antiretroviral prophylaxis if indicated. It is therefore necessary to have PEP services.
Evidence shows that initiating ART prophylaxis
soon after exposure to HIV reduces the risk of HIV infection by about 80%.
Postexposure prophylaxis (PEP) is short-term ART to reduce the likelihood of
acquiring HIV infection after potential exposure.
Post-exposure prophylaxis should be provided immediately or preferably within
72 hours of exposure. An HIV serology test should be performed on the exposed
individual as soon as possible (ideally within 48 hours).
Case of Accidental Exposure to Blood (AEB) or Other Biological Fluids
In case of accidental exposure to blood, always clean the exposed area immediately.In case of exposure through needle stick or skin injury, clean the wound immediately
with clean water and soap. In case of splash on the mucous membranes (particularly
the conjunctiva), rinse at least for 5 minutes with copious amounts of water or
preferably physiological saline or any available saline and do not apply disinfectant
on the mucous membranes. One of the health care providers from the health facilitymust evaluate the actual risk for a given patient.
This evaluation includes:
• The severity of the exposure, which is directly linked to the depth of the wound
and the type of needle that was responsible for the injury (venipuncture
needle, needle for injection, non sharp instrument).
• For external contact of secretions with the skin or mucosa (splash), the risk is
higher with blood than with any other body secretions (amniotic fluid, serous
fluid). The person assumed to be the source should be assessed on his
or her HIV status, clinical and immunological status and history of ART. If
the HIV status is not known, it is important to establish it with his/her free
consent. If the HIV status of the source person cannot be obtained within
4 hours, prophylaxis for the exposed person should be started immediately
after a negative HIV test. If eventually the person assumed to be the source is
proven to be HIV-negative, then ARV prophylactic treatment may be stopped
Case of Sexual Assault or Rape
In case of rape, the provider must first follow the HIV counselling and testing.PEP
should be offered to the sexual assault victim once the clinician has assessed all
the factors involved in the likelihood of HIV transmission (suspicion of HIV positivity
in the assailant, probability of HIV transmission). PEP might help the victim gain
a sense of control and decrease their anxiety about acquiring HIV. Consider HIV
post-exposure prophylaxis for survivors of sexual assault presenting within 72
hours of the assault. In addition to HIV post-exposure prophylaxis, women should
be offered emergency contraception to prevent unintended pregnancy immediately
or preferably within 72 hours after sexual exposure.
ART Prophylaxis in PEP
The current recommended duration of post-exposure prophylaxis for HIV infection
is 28 days. Treatment should start as early as possible, within the first 4 hours
following the exposure, without waiting for results of HIV serology of the source
person. A limit of 72 hours is reasonable in seeking maximum efficacy, however the
sooner the better.
The recommended post-exposure prophylaxis drugs are based on the current
second and first line regimen:
1.TDF+ 3TC / FTC +ATV/r
2. AZT + 3TC/ FTC + ATV/r(If noTDFor a contraindication)
NB: The recommended ART Prophylaxis is the same in rape/sexual assault andexposure to biological fluids.
Self-assessment 5.8
1) When HIV post-exposure prophylaxis for survivors of sexual assault is
taken into consideration?
2) What are the actual risks the health care providers from the health facilitymust evaluate in case of exposure through needle stick or skin injury?
5.9. End unit assessment
End of unit assessment
I. Complete the empty spaces with the appropriate terms.
a) Antiretroviral drugs
b) Antiviral
c) Retrovirus
1) ………………………An agent that kills a virus or that suppresses its ability
to replicate and, hence, inhibits its capability to multiply and reproduce.
2) ………………………is a group of viruses that belong to the family
Retroviridae and that characteristically carry their genetic blueprint in the
form of ribonucleic acid (RNA).
3) ………………………….. are the drugs that are used to fight retrovirus
infections which mainly include HIV. Different classes of antiretroviral
drugs act on different stages of the HIV life cycle.
II. Respond by true or false
1) Abacavir (Ziagen), lamivudine (Epivir) and stavudine (Zerit XR), tenofovir
(Viread).
2) Efavirenz (Sustiva), nevirapine (Viramune) are drugs in the class of
protease inhibitors
3) Abacavir (Ziagen) lamivudine (Epivir), stavudine (Zerit XR), tenofovir
(Viread), and zidovudine (Retrovir) drugs in the class of Nonnucleoside
reverse transcriptase inhibitors .
4) Atazanavir, indinavir and lopinavirare drugs in protease inhibitors.
5) Like older patients, HIV positive young patients should be treated with a
combination of antiretroviral drugs.
6) Antiretroviral therapy (ART) is recommended for all persons with HIV tocure the patient by killing the virus.
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