It is comprehensive slide on HIV and AIDS. It includes definition, clinical features, investigation and management.

1. HIV INFECTION AND AIDS
Dr. Navin Adhikari
IM Second Year Resident
NAMS

2. EPIDEMOLOGY
• AIDS was first recognized in the United States in 1981.
• Globally, 38.0 million people were living with HIV in 2019,
with 1.7 million newly infected in same year. 690000 people
died from AIDS-related illnesses in 2019. 26 million people
were accessing antiretroviral therapy as of the end of June
2020.
• In Nepal 28,500 people were living with HIV in 2019 with
790 new infection. 19410 were under ART as of July, 2020.

3. ETIOLOGIC AGENT
• HIV is the etiologic agent of AIDS, belongs to human
retroviruses (Retroviridae) and the subfamily of lentiviruses.
• HIV-1 and HIV-2 are strains. HIV-1 is the cause of the global
HIV pandemic, while HIV-2, which causes a similar illness to
HIV-1 but progresses more slowly and is less transmissible, is
restricted mainly to western Africa.
• HIV-2 has only 40% structural homology with HIV-1.
• On the basis of DNA sequencing, HIV-1 is divided into three
groups, which probably represent three zoonotic transfer
from the chimpanzee: M (‘major’, worldwide distribution), O
(‘outlier’) and N (‘non-major and non-outlier’).

4. MORPHOLOGY OF HIV
• HIV virion is an icosahedral structure
containing numerous external spikes
formed by the two major envelope
proteins, the external gp120 and the
transmembrane gp41.
• Two molecules of single stranded RNA
within the nucleus.
• The reverse transcriptase polymerase
converts viral RNA into DNA (a
characteristic of retroviruses).
• The protease includes integrase (p32
and p10).
• The p24 is core protein, its levels can
be used to monitor HIV disease.
• P17 is the matrix protein.

5. HIV GENOME
• Genes that encode the structural proteins of the virus:
Gag encodes the proteins that form the core of the virion
(including p24 antigen)
Pol encodes the enzymes responsible for protease processing
of viral proteins, reverse transcription, and integration.
Env encodes the envelope glycoproteins.
• It also contains at least six other regulatory genes (tat, rev,
nef, vif, vpr, and vpu) which code for proteins involved in the
modification of the host cell to enhance virus growth and the
regulation of viral gene expression.

6. HIV ENTRY AND REPLICATION
• The HIV binds to host CD4 molecules via the envelope
glycoprotein gp120.
• Gp120 binding to secondary receptors (chemokine receptors,
CXCR4, CCR5) and subsequent conformational change results
infusion between gp41 and the cell membrane.
• Entry of the viral capsid is followed by uncoating of RNA.
• DNA copies are made from both RNA templates (reverse
transcriptase).
• In the nucleus the virally encoded DNA is inserted into the
host genome (integration).
• Regulatory proteins control transcription (a process in which
an RNA molecule is synthesized from a DNA template).
• The virus is reassembled in the cytoplasm and budded out
from the host cell.

8. HIV INFECTION
HIV infection can be divided into the following stages:
1. Viral transmission
2. Acute HIV infection (also called primary HIV infection or
acute seroconversion syndrome)
3.Chronic HIV infection, is subdivided into :
•Chronic infection, without AIDS
•AIDS, characterized by a CD4 cell count <200 cells/microL
•Advanced HIV infection, characterized by a CD4 cell count
<50 cells/microL

9. VIRAL TRANSMISSION
• HIV is transmitted by sexual
contact, by exposure to
blood and blood products.
• Vertical transmission to
infants of HIV-infected
mothers (who may be
infected in utero, perinatally
or via breastfeeding).
• The risk of contracting HIV
after exposure to infected
body fluid is dependent on
the integrity of the exposed
site, the type and volume of
fluid, and the level of
viraemia in the source
person.

11. ACUTE HIV INFECTION
• 50–70% of individuals with HIV infection experience an acute
clinical syndrome within 3–6 weeks after primary infection.
• Symptomatic acute HIV infection is characterized by fever,
lymphadenopathy, sore throat, rash, myalgia/arthralgia,
diarrhea, and headache (often described as a mononucleosis-
like illness).
• Symptoms usually persist for one to several weeks and
gradually subside as an immune response to HIV develops
and the levels of plasma viremia decrease
• The differential diagnosis of primary HIV includes acute EBV,
primary CMV infection, rubella, primary toxoplasmosis and
secondary syphilis.

13. CHRONIC HIV INFECTION, WITHOUT AIDS
• Chronic HIV infection is characterized by relative stability of
the viral level and a progressive decline in the CD4 cell count.
• In the absence of antiretroviral therapy (ART), the average
time from HIV acquisition to a CD4 cell count <200
cells/microL is approximately 8 to 10 years.
• Persons with HIV at this stage of disease can have generalized
lymphadenopathy on physical examination. This is referred to
as "persistent generalized lymphadenopathy" when the
enlarged lymph nodes involve at least two noncontiguous
sites other than inguinal nodes for more than three to six
months without an alternative explanation.
• Some patients experience generalized/nonspecific symptoms
and signs such as fatigue, sweats, or weight loss.

14. EVENTS LEADING TO CHRONIC INFECTION

15. AIDS AND ADVANCED HIV INFECTION
• AIDS is chronic HIV infection with CD4 cell count <200
cells/microL or the presence of any AIDS-defining condition
regardless of the CD4 cell count.
• The term advanced HIV infection is often used to refer to
infection when the CD4 cell count is <50 cells/microL.
• When patients achieve immune reconstitution (eg, increase in
the CD4 cell count to >200 cells/microL) with antiretroviral
therapy (ART) and have no AIDS-defining conditions, they are
no longer considered to have AIDS.

16. AIDS-DEFINING CONDITIONS
• AIDS-defining conditions are illnesses that occur more
frequently or more severely because of immunosuppression.
• These include mainly opportunistic infections but also
certain malignancies as well as conditions without clear
alternative etiology thought to be related to uncontrolled HIV
infection itself.
• The AIDS-defining conditions listed by the United States
Centers for Disease Control and Prevention (used in high-
income countries) and the World Health Organization criteria (
used in low- and middle-income countries) vary slightly.

18. PROGRESSION OF UNTREATED HIV
INFECTION

19. Clinical Features
Direct consequence of HIV infection
1. AIDS dementia complex (ADC), sensory polyneuropathy and
aseptic meningitis.
2. Anaemia of chronic HIV infection is usually mild,
normochromic and normocytic
3. HIV-associated nephropathy
4. Symptomatic HIV-associated cardiomyopathy
5. HIV wasting syndrome
6. HIV cholangiopathy

20. HIV ASSOSSIATED DISEASES

21. DIAGNOSIS
• The detection of HIV infection depends on the presence of
antibodies and virus component, which depends on the days
since initial infection.
• Eclipse period- This period refers to the period of about 7–10
days following HIV infection, during which currently available
assays cannot detect any marker of HIV infection.
• Window period. The period between HIV infection and the
detection of HIV1/2 antibodies using immunological assays is
the window period.
• Recent infection. Any infection detected within six months of
infection is considered recent infection.

22. Diagnostic tests
1. Detection of IgG antibody to envelope components - based
on ELISA techniques, which may be confirmed with Western
blot assays.
2. IgG antibody to p24 (anti-p24)
3. Genome detection assays- Nucleic acid-based assays that
amplify and test for components of the HIV genome, aid
diagnosis of HIV in the babies of HIV-infected mothers or in
situations where serological tests may be inadequate, such
as in early infection.
4. Viral p24 antigen (p24ag)
5. Fourth generation HIV test- detect both HIV antibody and
HIV p24 antigen.

24. National HIV testing algorithm
• A three-test HIV testing algorithm is adopted.
• The first assay (A1) should be the most sensitive, and the
second and third tests should have higher specificity.

26. TREATMENT OF HIV

27. ART INITIATION
• National Centre for AIDS and STI Control (NCASC) has adopted
the WHO “TREAT ALL” policy since the revision of the national
HIV testing and treatment guidelines in 2017.
• The goals of ART are to reduce the viral load to an
undetectable level for as long as possible , improve the CD4
count to over 200 cells/mm3 so that severe HIV-related
disease is unlikely, improve the quantity and quality of life
without unacceptable drug toxicity and reduce HIV
transmission.
• ART should be initiated in all adults living with HIV, regardless
of WHO clinical stage and at any CD4 cell count.
• A comprehensive clinical assessment should be done as
baseline status and to rule out OIs.

28. • In patients with major opportunistic infections, ART should
generally be started within 2 weeks, with two important
exceptions: in cryptococcal meningitis, ART should be
deferred for 5 weeks, as earlier initiation increases the risk of
death; and in tuberculosis, ART should be deferred until 8
weeks (except if the CD4 count is < 50 cells/mm3 ), as earlier
initiation increases the risk of the immune reconstitution
inflammatory syndrome.

30. COMMONLY USED ANTIRETROVIRAL
DRUGS

31. ANTIRETROVIRAL REGIMEN
• In 2018, WHO published interim guidelines recommending
dolutegravir (DTG)- containing regimens as the preferred first-
and second-line ART regimens for PLHIV.
• In 2019 updated systematic review showed first-line regimen
of DTG combined with two nucleoside reverse transcriptase
inhibitors (NRTIs) leads to higher viral suppression and lower
risk of discontinuing treatment and developing HIV drug
resistance compared with efavirenz (EFV)-based regimens
among treatment-naive adults.
• DTG has other advantages over EFV, including lower potential
for drug–drug interactions, more rapid viral suppression and a
higher genetic barrier to developing HIV drug resistance
(HIVDR). DTG is also active against HIV-2 infection, which is
naturally resistant to EFV.

33. MONITORING
• Follow up is required for opportunistic infections and/or
immune reconstitution inflammatory syndrome (IRIS), as well
as early adverse drug reactions (ADR), such as drug
hypersensitivity and treatment treatment failure.
• Treatment failure is defined as persistently detectable Viral
Load (VL) exceeding 1000 copies/mL in two consecutive VL
measurements within a 3-month interval with adherence
support between measurements after 6 months of starting a
new ART regimen.
• The national programme recommends VL testing and CD4
count at 6 months and 12 months and only VL for stable
patients every 12 months. CD4 testing is stopped in virally
supressed patients

34. CD4 COUNT MONITORING
• Long-term CD4 cell count monitoring adds little value in
people who are stable on ART.
• However, CD4 count is important for assessing the baseline
risk of disease progression, particularly for individuals
presenting with advanced disease, and decisions regarding
starting and stopping prophylaxis for OIs.
• CD4 cell count measurement may also be important for
people who are failing ART and for unstable patients.

37. CLINICAL, IMMUNOLOGICAL AND
VIROLOGICAL FAILURE
• Clinical failure - New or recurrent clinical event indicating
severe immunodeficiency (WHO clinical stage 4 condition)
after 6 months of effective treatment.
• Immunological failure - CD4 count at or below 250 cells/ mm³
following clinical failure b or Persistent CD4 levels below 100
cells/mm³.
• Virological failure - Viral load above 1000 copies/mL based on
two consecutive viral load measurements in 3 months, with
adherence support following the first viral load test.

38. ARV TOXICITY
• Lamivudine- Flare of hepatitis in HBVco-infected patients
• Zidovudine- Anemia, granulocytopenia, myopathy, lactic
acidosis,
• Abacavir- Hypersensitivity reaction In HLA-B5701, ever, rash,
nausea, vomiting, malaise or fatigue, and loss of appetite
• Tenofovir- Renal toxicity, osteomalacia, flare of hepatitis in
HBVco-infected patients
• Nevirapine- Skin rash, hepatotoxicity
• Etravirine- Rash, nausea, hypersensitivity reactions
• Dolutegravir- Insomnia, headache, hypersensitivity reactions,
hepatotoxicity
• Efavirenz- Rash, dysphoria, elevated liver function tests,
drowsiness

41. CHEMOPROPHYLAXIS
Co-trimoxazole primary prophylaxis is started in
1. HIV-infected persons with a CD4 count < 350/mm3
2. all adults with severe and advanced HIV disease (WHO
stage 3 or 4)
3. In settings where malaria and/or severe bacterial infections
are highly prevalent regardless of CD4 cell count or WHO
stage.
4. all HIV-infected patients with active TB disease regardless of
CD4 cell count.
• Co-trimoxazole prophylaxis may be discontinued in adults
with HIV who are clinically stable on ART with evidence of
immune recovery and viral suppression.

42. • A macrolide (azithromycin or clarithromycin) is recommended
to prevent Mycobacterium avium complex ( MAC )in patients
with a CD4 count below 50 cells/mm3 , which can be
discontinued once the CD4 count has risen to over 100
cells/mm3 on ART.
• Serum cryptococcal antigen test should be done in patients
with a CD4 count below 100 cells/mm3 . If this is positive,
pre-emptive therapy with fluconazole should be commenced.

43. HIV-TB COINFECTION
• Tuberculosis is the most frequent life-threatening OI
• PLHIV are around 20 times more likely to develop TB disease
than those without HIV infection
• TB preventive treatment (TPT) is an important intervention
for preventing and reducing active TB among PLHIV.
• Active TB must be excluded before beginning TB preventive
treatment.
• The 2020 update of WHO guidelines on TPT makes 9H, 6H, 4R,
3HP, 3HR, 1HP as options for use across all disease burden
settings.
• The national HIV programme currently recommends the 6-
month isoniazid (6H) regimen for TPT.

44. TB preventive treatment

45. TB management in PLHIV
• All HIV-infected people with diagnosed active TB should be
put on TB treatment immediately.
• Antituberculosis treatment (ATT) should be initiated first,
followed by ART as soon as possible within the first 8 weeks
of treatment (2 weeks, if CD4 count < 50 cells/mm3).
• IRIS may occur after initiation of ART. Both ART and TB
treatment should be continued while managing IRIS.
• DTG 50 mg BID (instead of 50 mg once daily) should be used
for patients using rifampicin-based TB drugs.
• In case a patient on a PI-based regimen needs to start ATT, the
dose of PI should be doubled.

46. Immune reconstitution inflammatory
syndrome (IRIS)
• The term "immune reconstitution inflammatory syndrome"
(IRIS) describes a collection of inflammatory disorders
associated with paradoxical worsening of preexisting
infectious processes following the initiation of antiretroviral
therapy (ART) in HIV-infected individuals.
• It occurs in 10–30% of patients initiating ART, usually within
the first 4–8 weeks but can occur up to six months.
• After a patient starts ART, IRIS may manifest as a worsening of
previously diagnosed disease, termed paradoxical IRIS, or as
the appearance of a previously undiagnosed disease, termed
unmasking IRIS.

47. • IRIS should be considered only when the presentation
cannot be explained by a new infection, expected
course of a known infection or drug toxicity.
• IRIS should be diagnosed by excluding: active OIs,
treatment failure, side-effects of ARVs, ARV resistance
• The most serious and life-threatening forms of
paradoxical IRIS are for TB, cryptococcosis, Kaposi
sarcoma and herpes zoster.
• IRIS is generally self-limiting, and interruption of ART is
rarely indicated. Glucocorticoids are often used for
more severe IRIS manifestations.

48. Prevention of HIV
• Pre-exposure prophylaxis- daily tenofovir plus emtricitabine
has been shown to reduce the risk of HIV acquisition in
people at ongoing high risk and is well tolerated.
• Post-exposure prophylaxis- Start as soon as possible,
preferably within 2 hours and maximum within 72 hours of
exposure. The duration of treatment is 28 days. The choice of
PEP drugs should be based on the country’s first-line ART
regimen to treat HIV infection. Get a baseline HIV antibody
test and monitor for seroconversion at 6 weeks, 3 months and
6 months after exposure.

50. References
• Harrison's Principles of Internal Medicine, 20th
Edition.
• Davidson Principles and Practice of medicine
23rd Edition.
• Kumar & Clark's Clinical Medicine, 7th Edition
• Manson’s Tropical Disease, 23ed
• National-HIV-Testing-Guidelines-May-10-2020,
Nepal
• Uptodate
• https://www.unaids.org/en

51. THANK YOU