This document summarizes HIV infection and treatment. It describes how HIV was identified in the 1980s as the cause of AIDS. HIV can be transmitted through bodily fluids. Left untreated, HIV weakens the immune system and allows opportunistic infections. Treatment aims to suppress the virus and restore immune function. Highly Active Antiretroviral Therapy (HAART) uses a combination of three antiretroviral drugs from two classes to control the virus. Guidelines recommend starting treatment based on CD4 count. The goals of treatment are to improve quality of life and prevent disease progression.

1. HIV Infection
RVS Chaitanya koppala

2. Epidemiology
• In June 1981, five cases of Pneumocystis jiroveci (formerly known as
carinii) pneumonia (PCP) in the USA.
• Reports of other unusual conditions, such as Kaposi's sarcoma (KS),
followed shortly.
• So the term acquired immune deficiency syndrome, or AIDS, was
coined.
• In 1984, a new human retrovirus, subsequently named human
immunodeficiency virus (HIV), was isolated and identified as the
cause of AIDS.

3. The virus can be isolated from : blood, semen, vaginal secretions,
saliva, breast milk, tears, urine, peritoneal fluid and cerebrospinal
fluid (CSF).
The predominant routes of transmission remain (?)

4. Pathogenesis

6. Clinical manifestations
Five categories:
1. Opportunistic infections, that is, infections that would not normally
cause disease in an immunocompetent host
2. Infections that can occur in immunocompetent patients
3. Malignancies
4. Direct manifestations of HIV infection
5. Consequences of chronic immune activation

7. Approximately 70% of individuals develop a flu-like illness at sero -
conversion like fever, arthralgia, pharyngitis, rash and
lymphadenopathy.
Opportunistic infections generally fall into two categories:
• DNA viruses, for example, CMV and JC virus
• Intracellular pathogens, for example, P. jiroveci, Toxoplasma gondii
and Mycobacterium avium.

8. Investigations and monitoring
Current and previous infections:
After confirmation of HIV infection, the patient is usually tested for
prior exposure to a number of potential pathogens, including syphilis,
hepatitis A, B and C, CMV, varicella zoster (VZV), and gondii.
CD4 count: normal range is 500-1500cell/mm3
Viral load: The measurement of plasma HIV RNA (viral load) estimates
the amount of circulating virus in the blood. Conversely, a reduction in
viral load after commencement of antiviral therapy is associated with
clinical benefit

9. Resistance testing : Due to the implications of transmitted (primary)
resistance, it is recommended that all patients have a genotypic HIV
resistance test performed soon after diagnosis; this will ensure that
appropriate initial therapy is selected.
Tropism testing: Viruses may enter the cell using the CCR5 co-receptor,
the CXCR4 co-receptor or both co-receptors. Those which just use one
co-receptor are known as CCR5-tropic or CXCR4- tropic viruses; those
which can use both receptor types are called dual-tropic

10. Drug treatment
The drug treatment of HIV disease can be classified as antiretroviral
therapy, the management of opportunistic infections or malignancies,
the management of ‘non-HIV-related’ co-morbidities, and symptom
control.
For the first decade were aimed at treating or preventing opportunistic
complications.
Whilst these are still important, there has been a shift in emphasis
towards treatment aimed at reducing the HIV viral load

11. Highly Active Antiretroviral Therapy (HAART)
This immunological restoration may result in apparent clinical deterioration with
opportunistic infections during the first few weeks after initiation of HAART.
This is known as immune reconstitution inflammatory syndrome (IRIS).
The goals of therapy in HIV-positive individuals are to:
• Improve the quality and duration of life;
• Prevent deterioration of immune function and/or restore immune status
• Treat and/or prevent opportunistic infections;
• Relieve symptoms.

12. Antiretroviral therapy
Antiretroviral therapy is currently one of the fastest evolving areas of medicine.
• A combination of three antiretroviral agents, selected on the basis of treatment history and
resistance tests
• Wherever possible, a regimen should contain at least one drug that penetrates the central nervous
system (?)
• Treatment strategies should be adopted that sequence drug combinations, being mindful of
potential cross resistance and future therapy options
• Given the crucial importance of a high level of adherence to these therapies, the regimen adopted
for a particular individual should, wherever possible, be tailored to suit the daily lifestyle.

13. International AIDS Society (IAS)
updated guidelines on the use of antiretroviral therapy, for example
These guidelines include the most up- to-date considerations of:
• When to start therapy
• What to start with
• How to monitor, including use of therapeutic drug monitoring and
resistance testing;
• When to switch therapy
• What therapy to switch to
• Treating individuals who have been highly exposed to multiple agents
• Managing individuals with significant co-morbidities, for example,
tuberculosis or hepatitis B/C.

14. Most studies evaluating triple combinations of antiretrovirals have
been designed with so-called surrogate marker endpoints, measuring
the effect on laboratory parameters such as CD4 count and HIV viral
load.

15. When to start therapy
Current UK guidelines recommend starting antiretrovirals when the
CD4 count drops below 350 cells/mm3.
Therapy should be considered at a higher CD4 count in specific
situations, for example, in the presence of an AIDS-defining illness or
HIV-related morbidity.

16. Choosing and monitoring therapy
The majority of individuals are currently commenced on a
combination of two nucleoside/nucleotide reverse transcriptase
inhibitors (NRTIs) and a non-nucleoside reverse transcriptase inhibitor
(NNRTI) or two NRTIs and a boosted PI.
Triple NRTI therapy is no longer recommended, as it is associated
with unacceptable rates of virological failure

17. The aim of initial therapy
To achieve viral load suppression in the plasma to levels below the
detection limits of available assays (40 or 50 copies/mL).
Such virological suppression is almost invariably accompanied by an
elevation in CD4 count and clinical evidence of immune
reconstitution.

18. • In addition, there are a number of combination formulations of NRTIs
that may be used to reduce pill burden:
Abacavir + lamivudine (Kivexa®)
Tenofovir + emtricitabine (Truvada®)
Zidovudine + lamivudine (Combivir®)
Zidovudine + lamivudine plus abacavir (Trizivir®)
• There is also one formulation combining two NRTIs with an NNRTI:
Tenofovir + emtricitabine + efavirenz (Atripla®)
• Other triple and quadruple mixed class co-formulations are in
development.
• Most antiretroviral regimens will include two NRTIs, together with a
PI and/or an NNRTI.

19. Non-nucleoside reverse transcriptase inhibitors
NNRTIs inhibit the reverse transcriptase enzyme by binding to its active
site.
The NNRTIs available include:
• Efavirenz (Sustiva®)
• Nevirapine (Viramune®)
• Etravirine (Intelence®)

20. Protease inhibitors
PIs bind to the active site of the HIV-1 protease enzyme, preventing the
maturation of the newly produced virions so that they remain non-
infectious.
The following PIs are currently available:
• Atazanavir (Reyataz®)
• Nelfinavir (Viracept®)
• Ritonavir (Norvir®)
• Saquinavir (Invirase®)
• Tipranavir (Aptivus®)

21. Entry inhibitors
• Enfuvirtide (T-20, Fuzeon®), a fusion inhibitor, is administered
Subcutaneously
• Maraviroc (Celsentri®), a CCR5 inhibitor, is indicated for use in
patients with only CCR5-tropic virus,

22. Integrase inhibitors
Integrase inhibitors bind to the integrase enzyme, thus blocking the
integration of viral DNA into host DNA.
There is currently one licensed agent, raltegravir (Isentress).
Other agents in development include elvitegravir and dolutegravir.
Elvitegravir requires boosting and is being developed as a co-ormulation
with cobicistat.