HIV Infection RVS Chaitanya koppala

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.

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 (?)

Pathogenesis

Clinical manifestations

Five categories:1. Opportunistic infections, that is, infections that would not normally

cause disease in an immunocompetent host2. Infections that can occur in immunocompetent patients3. Malignancies4. Direct manifestations of HIV infection5. Consequences of chronic immune activation

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.

Investigations and monitoringCurrent 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/mm3Viral 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

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

Drug treatmentThe 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

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.

Antiretroviral therapyAntiretroviral 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.

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.

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.

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.

Choosing and monitoring therapyThe 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

The aim of initial therapyTo 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.

• 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.

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®)

Protease inhibitorsPIs 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®)

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,

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.