PREPARED BY : DR.

PARITOSH VASANI
DR. RAJ PATEL
DR. HARSH VAGADIA

UNDER GUIDANCE OF :- DR. RONAK KAPADIA

Viral entry :
• Coreceptors : CCR5, CXCR4 present on the CD4+ T-cell
• Gp120 + CD4 cells binding cause conformational change,
• Leading to Hair pin loop formation
• Virus brought closer to Host cell  Fusion of Membranes.
• Viral genetic material and enzymes release into Host cells
• Replication of virus.
• HIV-1 binds to its target cell via CD4 molecule,leading to
conformational change in Gp120,
Allows it to bind to co-receptor CCR5
• Whom to treat ?
“Treat ALL” : Regardless of the clinical stage or CD4 count is in the National
Programme since 2017.

• Where your patient is ?

• WHO Clinical staging for Adults,Adolescents.
• Useful to determine where your patient belongs in terms of opportunistic
infections & Immune status.
 Nucleoside reverse
transcriptase inhibitors (NRTI)
• Inhibits viral reverse transcriptase enzyme by undergoing intracellular
phosphorylation and thus prevents conversion of single stranded viral RNA to pro-viral
DNA. Thus it helps in preventing infection of new cells by HIV, but no effect on already
infected cells, where in proviral DNA is already formed. It is competitive inhibitors.

• Zidovudine (AZT)
• Didanosine(ddl)
• Stavudine(d4t)
• Lamivudine(3tc)
• Abacavir(ABC)
• Tenofovir(tdf)
• Emtricitabine(FTC)
 Lamivudine
• Dose: 300mg Odor 150mg bd
• Primarily eliminated by kidney, and dose adjustment is needed to prevent
accumulated
• Can be used for hepatitis-B infection, but in reduced dosage.
• Point mutation in HIV reverse transcriptase and HBV DNA polymerase give rise
to rapid lamivudine resistance.
• Adverse effect : headache(35%), fatigue(~27%), malaise(~27%), peripheral
neuropathy, dizziness, increase hepatic enzymes
• Contraindicated in person hypersensitive to Lamivudine,
 Tenofovir
• Dose : 300mg od
• Tenofovir alafenamide, Tenofovir disoproxil fumarate
• Renal dose adjustment is recommended (for TDF)
• Discontinue use in patients who develop clinically significant decrease in renal
function or develop fanconi syndrome.
• Adverse effect : abdominal pain, diarrhoea, rash, increase creatinine,
arthralgia, bone demineralization.
Tenofovir toxicity
• Overall good safety profile, fewer metabolic side effects and mitochondrial
toxicities.
• Major S/E are :
1. Renal toxicity (most significant) : overall 3-5%
2. Decrease in Bone Mineral density.

However TAF is associated with less renal and bone toxicity compared with
TDF since it achieves lower plasma tenofovir concentrations.
 NNRTIs (non-nucleoside reverse
transcriptase inhibitors)
• MOA: Directly inhibit HIV reverse transcriptase without the need for intracellular
phosphorylation. Their site of action is different from NRTIs. They are non-
competitive inhibitors.
• Metabolised by CYP3A4 and CYP2B6.
• Are enzymes inducers.

• Nevirapine
• Efavirenz
• Delavirdine
• Rilpivirine
• Etravirine
• Doravirine
 EFAVIRENZ(EFV)

• 600mg OD or 400mg OD in combination with TDF + 3TC.

• In moderate to severe hepatic impairment usage is not recommended.
• Adverse effect : skin rash, dyslipidemia, diarrhoea, NEUTROPENIA, increased
liver enzymes.
• Efavirenz is mainly metabolised by CYP2B6, hence when patient on nevirapine
develops TB and is put on rifampicin, NVP is substituted with EFV.
• Avoid taking efavirenz after High fat meals.
• Efavirenz has significant CNS/Psychiatric adverse effects :

1. Frank psychosis (Hallucinations,depression and/or mania)

2. Impaired concentrations
3. Dizziness
4. Vivid dreams
5. Insomnia

Recommended to take efavirenz before bed time to minimize side effects.

Symptoms are self limiting and tend to disappear after several weeks of therapy.

Efavirenz has been replaced by DOLUTEGRAVIR as per new guidelines.

• Nevirapine :

• Dose : 200mg OD initially for 14 days, f/b 200mg BD or 400ER OD.

• Adverse effect :
severe life- threatening hepatotoxicity(usually within first 12 weeks), severe skin
reaction such as SJS/ TEN can occur. Check transaminases levels immediately in
patient who develop a rash in the first 18 weeks of treatment.
• Do not restart NVP after clinical hepatitis.
• Others :dyslipidemia, neutropenia, fatigue, headache, nausea, fever(1-2%).
 INTEGRASE INHIBITOR
• MOA: The Integrase Inhibitor enzyme catalyses the process by which viral DNA is
integrated into the genome of the host cell. These drugs prevent or inhibit the binding of the
pre-integration complex (PIC) to host cell DNA, thus terminating the integration step of
HIV replication.

• Raltegravir, Elvitegravir, Dolutegravir and Bictegravir,Cabotegravir

• They are better for patients with either abnormal lipid profiles or risk factor for CAD, since
they have a neutral effect on cholesterol and triglyceride, compared to NNRTIs and
protease inhibitors.

• Active against both HIV-1 and HIV-2

• Half life : 12 hours
• Injectable-long acting INSTI(integrate strand transfer inhibitor) such as Cabotregravir is also
available.
Dolutegravir
• NACO recommends dolutegravir as the preferred drug for HIV- positive adults, adolescents
and children(age >6yrs & Wt. >20kg)
• Dose : 50 mg once daily without regard to food and should be increased to 50 mg twice
daily for treatment - experienced patients who have previously used other integrase
inhibitors.

• Several trials have shown that dolutegravir is well tolerated.

However, dolutegravir may be associated with more central nervous side effects (CNS)
compared with other INSTIs (eg, insomnia and dizziness)

• Dolutegravir can cause serious life threatening side effects,which include Hypersensitivity
(Allergic reactions) and Hepatitits.

• Dolutegravir can have significant interactions with agents, such as metformin, rifampin, and
• DTG and weight Gain – concern of weight gain has been noted with use of DTG.
However, it is worth noting that the weight gain was mostly seen when TAF was
used along with DTG.

Benefits of DTG :-
• Highly potent and has High genetic barrier.
• Causes Rapid Viral Suppression;Helps in achieving rapid viral suppression.
• Found to reduce viral copies to <50 copies/ml within 4 weeks.
• Effective in PLHIV infected with HIV-2 or combined HIV-1 and HIV-2.
• No need for substitution of DTG-based ART regimen in PLHIV if co-infected with
TB or HBV or HCV.
 Raltegravir
is approved for use in treatment-naïve and treatment-experienced patients with HIV Raltegravir •

It had been primarily used for Second or Third line ART in national ART program.

• Raltegravir is generally administered as 400 mg twice daily (800 mg total daily dose). However, once daily
dosing with two 600 mg tablets (1200 mg total daily dose) is an option for patients who are treatment naïve or
who are virologically suppressed (eg, HIV RNA <50 copies/mL) on an initial regimen of raltegravir 400 mg
twice daily.

If raltegravir is co-administered with rifampin, it should be administered as 800 mg twice daily.

Although rare, side effects can be seen with raltegravir, and include nausea, dizziness, and headache. Rare cases of
skeletal muscle toxicity and severe systemic cutaneous reaction resembling Stevens-Johnson syndrome have
also been reported

One of the main disadvantages of raltegravir is its lower genetic barrier to resistance compared with dolutegravir
and protease inhibitors
 Protease inhibitor
• Protease inhibitors (PIs) are typically administered in combination with a dual nucleoside combination; however,
they can also be used as part of a nucleoside-sparing/limiting regimen. PIs should be administered with a
boosting agent, either ritonavir or cobicistat. They can be used for patients who are treatment-naïve, and are often
the preferred agent for patients failing their initial antiretroviral therapy (ART) regimen.

• Mechanism of action – Protease inhibitors (PIs) competitively inhibit the cleavage of the Gag-Pol polyproteins
in HIV-infected cells, which is a crucial step in the viral maturation process, thereby resulting in the production
of immature virions that are not infectious

• Resistance – PIs have a relatively high genetic barrier to resistance compared with non-nucleoside reverse
transcriptase inhibitors (NNRTIs) and the integrase inhibitors (INSTIs) raltegravir and elvitegravir.

• Adverse events – There are several side effects that appear to be PI class effects while others are agent-specific.
Some of the class side effects are insulin resistance, hyperglycemia, diabetes, hyperlipidemia, lipodystrophy,
hepatotoxicity, bleeding in patients with hemophilia, and PR interval prolongation
 Ritonavir

• It is a potent PI; also a potent CYP3A4 inhibitor.

• It is most commonly used as a low dose of 100mg BD to boost the effect of other PIs except
NFV(Nelfinavir).
• Side effects : Nausea,drug interaction,diarrhoea, paresthesia, fatigue and lipid abnormalities
are prominent.
 Atazanavir
• Atazanavir — Atazanavir should be administered as atazanavir 300 mg once daily plus
ritonavir 100 mg once daily or atazanavir 300 mg once daily plus cobicistat 150 mg
once daily. Atazanavir and cobicistat are coformulated as a single tablet . When
atazanavir is administered with cobicistat, it should be avoided in patients with an eGFR
<70 mL/min/1.73 m2 if tenofovir disoproxil fumarate-emtricitabine is used as the
nucleoside combination.

• Atazanavir has the advantage of better gastrointestinal tolerance than most other PIs,
once-daily dosing, and good potency.

• Adverse Effects are - Unconjugated hyperbilirubinemia, lipid

abnormality,hyperglycemia,fat maldistribution, nephrolithiasis, cholelithiasis, PR
prolongation
 Darunavir
Dose : Darunavir can be given once daily (800 mg darunavir with 100 mg ritonavir or 150 mg
cobicistat) if there are no darunavir mutations, even if there is resistance to other agents

The principal adverse effects associated with darunavir include nausea, diarrhea, increased
transaminases, headache, and rash. However, severe reactions can occur, and darunavir
should be discontinued in patients who develop a rash associated with fever, transaminase
elevations, eosinophilia, and/or systemic symptoms, as well as those who have severe skin
reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, exanthematous
pustulosis)
 Entry Inhibitors

• Fusion Inhibitor : GP 41 blocker 

Enfuvirtide

• Attachment Inhibitor :
1. CCR-5 blocker : Maraviroc
2. GP-120 blocker : Fostemsavir
3. CD4 blocker : Ibalizumab
ENFUVIRTIDE
• Interferes with the fusion of the viral and cellular membranes by
binding to the HR1 region in the gp41 subunit of the HIV-1 envelope.
• Not active againt hiv-2.
• Among the drawbacks
1) Twice a day injection
2) Injection site reactions in close to 100% of patients,
3) An increase in bacterial pneumonia
Maraviroc
• A CCR5 Antagonist
Interferes with HIV binding at the stage of co-receptor engagement.
• A co-receptor tropism assay
Should be performed if one is considering the usee of maraviroc
• ADR
An allergic reaction associated hepatotoxicity has been
Among the most common side effects of maraviroc are,
1) Dizziness due to postural hypotension
2) cough, fever , colds, rash, muscle and joint pain
Diagnosis of HIV
Objectives of HIV Testing

• Blood and blood products safety. This is achieved by mandatory testing of all donated blood units and blood products.

• Screening of sperm, organs, and tissue donors.

• In clinically suspected cases.

• Voluntary testing after counselling.

• Epidemiological surveillance.

• Research.
Choice of the Screening Assay
Before choosing a particular kit/strategy for HIV testing one has to be clear about the objectives
of testing. The following parameters should be considered before testing:
• Sensitivity of the test kit
• Specificity of the test kit
• Prevalence of HIV infection in the population
• Cost effectiveness
• Appropriateness of testing to national guideline strategies and to the infrastructure facilities
available.

Sensitivity of HIV Tests

The sensitivity of a diagnostic test describes its ability to detect all positive samples as positives. Tests with high
sensitivity may show a few false positives but will not miss any true positives.

Specificity of HIV tests

It is the accuracy with which a test can confirm the absence of an infection or identifying true negative. Tests with
high specificity show less number of false negatives and are to be preferred for the diagnosis of HIV infection in
an individual.
Commonly used screening tests are:
• Enzyme Linked Immunosorbent Assay (ELISA)
Types: direct, indirect, sandwich, competitive
• Rapid tests
1. Immunoconcentration/Dot Blot assay (vertical flow)
2. Agglutination assay
3. Immunochromatographic assay (lateral flow)
4. Dipstick and comb assay based on Enzyme Immune Assay (EIA)

Western Blot:
In the western blot, the various HIV specific recombinant or synthetic
antigens are adsorbed onto nitrocellulose paper. This is similar to what is
done in an ELISA test, except that the product is insoluble.
 HIV TESTING
STRATEGIES
Strategy 1 (for blood transfusion/transplant safety)
The specimen is subjected to one test for HIV reactivity. The test used in
strategy 1 must have high sensitivity. If non reactive, the specimen is to be
considered free of HIV (negative) and if reactive, the specimen is
considered as HIV popsitive. This strategy is used for ensuring donation
safety (e.g., blood, blood products, organs, tissues, sperms etc.). The unit
of blood that tests reactive (positive) is discarded. If the donor is to be
notified of his result, based on his prior consent, it becomes a matter of
diagnosis (in which case strategies II & III must be used after proper
counselling) and the donor should be referred to an ICTC for the
confirmation of the
Strategy 2A for surveillance :
A specimen is considered negative for HIV if the first ELISA
or rapid test reports it so. In case it is reactive, it is subjected
to a second ELISA or rapid test, which utilizes a system
different from the first one (i.e., the principle of the test
and/or the antigen used is different). It is reported positive
only if the second ELISA/rapid test also gives a reactive
report like the first test. In case the second E/R is non
reactive, the result is taken as negative for sentinel
surveillance purposes. This type of HIV testing is
anonymous and unlinked.
Strategy 2 B (used for diagnosis in symptomatic
patients)
This strategy is used to determine the HIV status of a
clinically symptomatic suspected AIDS cases in which
blood/serum/plasma is tested with a highly sensitive
screening test.
Strategy 3 (used for diagnosis in asymptomatic
patients)
In strategy 3 the HIV testing done is similar to strategy 2,
with the added testing of a third test for a positive result.
Positive confirmation of a third reactive E/R test is
required for a specimen to be reported HIV positive. If the
specimen gives a reactive result with two E/R and non-
reactive result with the third assay, it is reported as
“indeterminate” and the patient is called again for repeat
testing after 2-4 weeks.
Qualitative Polymerase Chain Reaction for HIV DNA
In infants, the sensitivity of a traditional PCR test – for the diagnosis of HIV infection and the qualitative
detection of HIV DNA – is as high as 90 to 100 percent by the age of 4- 6 weeks. An example of a commercially
available test, approved by the Drug Controller General of India (DCGI), is the qualitative AMPLICOR HIV-1
DNA PCR Test, ver. 1.5 (Roche), which can be used to test dried blood spots or whole blood collected in EDTA.
This test has a reported 99.3 percent sensitivity and 96 percent specificity.

Qualitative Transcription-mediated Amplification Assay for HIV RNA

The APTIMA HIV-1 qualitative RNA assay (Gen-Probe) is licensed by the U.S. Food & Drug Administration
(FDA) for use as an aid in the detection of acute HIV-1 infection in plasma specimens.

Quantitative HIV-1 RNA Assays

Quantitative HIV-1 RNA assays detect plasma (cell-free) viral RNA by using various techniques. The methods
of amplification of HIV-1 RNA include:
1) Target amplification by
a. Reverse transcriptase PCR (RT-PCR)
b. RealtimePCR(qPCR)
c. Nucleic acid sequence-based amplification (NASBA)
2) Signal amplification by branched-chain DNA technique(bDNA)
Other Assays
Virus Isolation
HIV isolation requires co-cultivation of peripheral blood mononuclear cells (PBMCs), from an
infected individual and mitogen stimulated PBMCs from an HIV-uninfected individual. These are
cultured together for up to 6 weeks in a medium containing interleukin- 2. The replication of
HIV can be detected by measuring the p24 antigen by ELISA, or reverse transcriptase
activity in culture supernatant. The disadvantages of a viral culture as a diagnostic test far
exceed its advantages. It is labour-intensive, time consuming, expensive and requires containment
facilities. It has limited use, except as a research tool.

Antigen Detection
The HIV-1 p24 antigen is present as either an immune complex, with anti-p24 antibodies, or as a
free p24 antigen in the blood of infected individuals. The positive p24 test confirms diagnosis of
HIV infection; however, a negative test does not rule out HIV infection. The test is based on
the ELISA. The sensitivity of the test increases with the use of techniques to dissociate the p24
antigen from its antibody, as in immune complex-dissociated (ICD) tests
HIV p24 antigen assays, with increased sensitivity, are now commercially available and under
evaluation, e.g., the ultrasensitive p24 assay (Perkin- Elmer).
 MANAGEMENT OF HIV

• FIRST LINE ART in PLHIV for treatment-naïve adult and adolescent patients
with age >10 yrs and weight >30kg is as follows :-

• Tenofovir (TDF 300mg) + Lamivudine (3TC 300mg) + Dolutegravir (DTG 50mg)

regimen (TLD) as FDC in a single pill once a day.

• A single pill of TLD preferably taken at bedtime, and situations where additional
dosing of DTG is indicated should be taken preferably in the morning.
 Plasma Viral Load
• Signifies rate of CD4 + T cell destruction and magnitude of HIV replication.
• Within first few weeks of ART initiation, It starts decreasing.
• After first 6 months, a plasma viral load test should be done to evaluate
response to ARVs.
• Repeated again at 12 months and once viral load is suppressed, every 12
months.
• Most people achieve viral suppression by 6 months of initiation of ART.
 Stable Adults and adolescents
(>10 yrs)
• PLHIV (Adult/Adolescent) shall be termed ‘Stable’ if they fulfill all of the
following criteria :

1. On ART for at least 6 months ;

2. No Adverse effects of ART that require regular monitoring ;
3. No Current illness/Opportunistic infections/medical condition that require
regular monitoring ;
4. Suppressed plasma viral load (in absence of viral load monitoring, rising CD4
cell counts exceeding 200 cells/mm3 and adherence >95% consecutively over
last 3 months)
Treatment
failure
• Substitution : refers to replacement of ARV drug in virally supressed PLHIV due
to adverse effect of drug/ drug-drug interaction/ due to change in program
policy.

• Switch : when the regimen is changed due to ARV treatment failure, which is
switch of the entire regimen
• What to expect in first six months of therapy ?

Certain OIs and/or IRIS and/or early adverse drug reactions such as
drug hypersensitivity may develop,especially