Post Exposure Prophylaxis Therapy for HIV

The impact of exposure to human immunodeficiency virus (HIV) depends on two main factors: (1) Nature of exposure and (2) The status of the source patient (the patient to whose blood or body fluids exposure has occurred). There is need to evaluate the source patient within 2 hours of exposure so that post exposure prophylaxis (PEP) could be started. The initiation of PEP should not be delayed more than 72 hours in any case. The baseline HIV testing should also be done for the exposed person before starting post exposure prophylaxis therapy. The post exposure prophylaxis refers to the comprehensive management given to the exposed person to minimize the risk of infection following potential exposure to blood-borne viruses (HIV, HBV and HCV). The risk assessment could only be evaluated through relevant laboratory investigations. Antiretroviral therapy should be started after consultation with the physician and follow up and supportive counseling should be provided to the exposed person at the surveillance centers.

The relative risk of HIV transmission after different routes of exposure has been established as under:

Exposure Route	HIV Transmission
Blood transfusion	90-95%
Sexual intercourse-Vaginal	1-10%
Sexual intercourse-anal	0.05-0.5%
Sexual intercourse-oral	0.005-0.01%
Perinatal	20-40%
Intravenous drug use	0.5-1%
Needle stick injury	0.5%
Mucous membrane splash to eyes	0.1%

The exposure to blood, semen, vaginal secretions, cerebrospinal fluid, synovial fluid, pleural fluid, pericardial fluid and amniotic fluid is considered risky and infectious. However, exposure to tears, sweat, urine, faeces and saliva is not considered infectious unless these secretions contain blood. The exposure is considered mild if the contact is with the eyes or mucous membranes or there is needle stick injury with small bore needle generally during vaccination or skin testing. The exposure is considered moderate if the mucous membranes or intact skin is exposed to large volume of body fluid or blood of the infected patient. A cut with surgical blade or needle stick injury with blood smeared needle. The exposure is considered severe if the accidental prick is with high bore (> 18G) needle contaminated with blood or a deep wound is caused with surgical knife smeared with blood. Transfusion of infected blood or packed cells.

The prescription of post exposure prophylaxis depends on the category of exposure. For mild exposure, basic regimen or 2-drug combination is generally prescribed depending on the status of the source of exposure. If the exposure source is HIV+ but asymptomatic, consider 2-drug PEP and if the source is HIV+ and clinically symptomatic, immediately start 2-drug PEP. In case of moderate exposure to HIV+ but asymptomatic source, start 2-drug PEP. If the source is found HIV+ and clinically symptomatic in case of moderate exposure, start expanded regimen which is 3-drug combination. In case of severe exposure to an HIV+ but asymptomatic or clinically symptomatic source, immediately start 3-drug combination. PEP regimens prescribed by health centers are: (1) 2-drug regimen: Zidovudine (AZT) + Lamivudine (3TC) or Stavudine (d4T) + Lamivudine (3TC). (2) 3-drug regimen: Zidovudine (AZT) + Stavudine (d4T) + Lamivudine (3TC). Expert opinion is must before starting PEP therapy.

AIDS and HIV Vaccines

AIDS or acquired immunodeficiency Syndrome is caused by human immunodeficiency virus (HIV). The World Health Organization (WHO) is an International Organization associated with the community health programs throughout the world and it is the reward of concerted efforts that the diseases like smallpox and polio have completely been eradicated through vaccination. Now the worldwide focus is on the development of an effective vaccine to control the spread of AIDS and providing prophylaxis to health professionals. An ideal HIV vaccine would be the one which could mount a good humoral and cell mediated immune response both locally and systemically. HIV is an enveloped virus that contains two copies of genomic ribonucleic acid (RNA). There is a glycoprotein of 120 kD molecular weight commonly known as gp120, through which the virus binds to the cellular receptors at the surface of T-helper lymphocytes or CD4⁺ cells. The binding of virus to the CD4 receptor in association with chemokine co-receptor causes a dynamic change in gp120 and further activates trans-membrane protein gp41. These changes cause fusion of HIV envelope to the cell membrane of CD4⁺ cell and further make way for the entry of virus into the cytoplasm of CD4⁺ cell, replicate there, destroy cell and infect new cells.

Experimental studies in animals have shown that a considerable amount of T-cell response can be induced with HIV vaccines thereby limiting the viral RNA levels in plasma and minimizing the destruction of CD4⁺ T-cells. The survival of CD4⁺ T-cells through vaccination might help control infection and prolong disease-free survival of immunized person. The HIV vaccine capable of controlling the viral replication may also reduce the secondary transmission since the progression of secondary transmission is directly related to the plasma viral load. The oldest procedure of vaccine development has been tried wherein live attenuated viruses are used as vaccine but could not be put to the practice in case of HIV vaccine due to danger of infection if the virus particle were not completely killed or attenuated. Novel strategies are being used wherein certain immunogenic viral peptides (non-infectious and genetically engineered) have been tried and put to clinical trials. HIV vaccines developed on the guidelines of viral vectors containing vaccines and DNA vaccines are under way of active clinical trials. The vaccine war is going on against HIV.

Anti-Retroviral Drugs for Treatment and Prophylaxis

There are over a dozen anti-retroviral drugs duly approved for treatment of HIV-1 infection and for optimal prophylaxis against the virus. Anti-retroviral drugs include HIV-1 protease inhibitors, non nucleoside reverse transcriptase inhibitors (NNRTIs) and fusion inhibitors (HIV entry inhibitors). At present combination drug therapy is used to thrash the dynamics of HIV-1 replication. The four main classes of anti viral agents are: (1) Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs and NtRTIs), (2) Non nucleoside reverse transcriptase inhibitors (NNRTIs), (3) Protease inhibitors (PIs) and (4) HIV entry inhibitors.

Nucleoside reverse transcriptase inhibitors (NRTIs) available are: Zidovudine (AZT/ZDV), Stavudine (d4T), Lamivudine (3TC), Didanosine (ddI), Zalcitabine (ddC), Abacavir (ABC) and Emtricitabine (FTC).

Nucleotide reverse transcriptase inhibitor (NtRTI) available is: Tenofovir (TDF).

Non nucleoside reverse transcriptase inhibitors (NNRTIs) available are: Nevirapine (NVP), Efavirenz (EFV), Delavirdine (DLV) and Etravirine.

Protease inhibitors (PIs) available are: Saquinavir (SQV), Ritonavir (RTV), Nelfinavir (NFV), Amprenavir (APV), Indinavir (INV), Lopinavir/Ritonavir (LPV), Fosamprenavir (FPV), Atazanavir (ATV) and Tipranavir (TPV).

HIV entry inhibitors (Fusion inhibitors) available are: Enfuviritide (T-20) and CCR5 entry inhibitors.

Acquired immunodeficiency Syndrome or AIDS is caused by human immunodeficiency virus (HIV). HIV is an enveloped virus that contains two copies of genomic ribonucleic acid (RNA). There is a glycoprotein of 120 kD molecular weight commonly known as gp120, through which the viruses bind to the cellular receptors at the surface of T-helper lymphocytes or CD4⁺ cells. The binding of virus to the CD4 receptor in association with chemokine co-receptor causes a dynamic change in gp120 and further activates trans-membrane protein gp41. These changes cause fusion of HIV envelope to the cell membrane of CD4⁺ cell and further make way for the entry of virus into the cytoplasm of CD4⁺ cell. The main receptors used by HIV-1 are chemokine receptors CCR5 and CXCR4. It has been resolved through the assessment of amino acid sequences of different HIV-1 strains that there are five variable (V1-V5) and four constant (C1-C4) regions in gp120. The expression of CCR5 or CXCR4 on the surface of CD4⁺ target cells (T-helper lymphocytes) defines their susceptibility to infection by corresponding HIV-1 strain. The use of specific receptors by viruses for infecting the target cells determines the virus cell tropism. The dual tropic viral strains can use both the receptors at the surface of CD4⁺ target cells. It is well established now that R5 viruses remain present in approximately 50-60% of individuals who progress to AIDS, whereas remaining 40-50% of individuals switch to X4 viruses with the progression of the disease and show a decline in the count of CD4⁺ target cells. The mutations in viruses confer them resistance to CCR5 treatment in the absence of co-receptor switch. HIV entry inhibitor compounds have been gaining importance as therapeutic agents for the treatment and post exposure prophylaxis against HIV infection. The aim of HIV therapy is to suppress the viral infection to achieve the disease free prolonged survival and this can not be achieved with monotherapy only due to complex life cycle of HIV.

HAART Therapy

The most effective HIV therapy is the highly active anti-retroviral therapy (HAART) wherein anti-retroviral agents are administered in combination of different drug classes. Generally HAART is any combination regimen designed to achieve the goal of complete virus suppression and these regimens comprise a minimum of three drugs. NNRTI based regimen comprises two NRTI or NtRTIs plus one NNRTI. PI based regimen comprises two NRTI or NtRTIs plus one or more PIs. Monotherapy is restricted to the prevention of perinatal transmission of HIV. Zidovudine (ZDV or AZT) and nevirapine (NVP) are generally used drugs for the monotherapy. The indications for HAART are history of AIDS-defining illness with CD4⁺ cell counts <350/µl or pregnant women without consideration for CD4⁺ cell count. Persons with HIV-associated nephropathy and persons co-infected with hepatitis virus-B (HBV) are considered fit cases for initiation of HAART.

AIDS and HIV Entry Inhibitors’ Target Action

Acquired immunodeficiency Syndrome or AIDS is caused by human immunodeficiency virus (HIV). HIV is an enveloped virus that contains two copies of genomic ribonucleic acid (RNA). There is a glycoprotein of 120 kD molecular weight commonly known as gp120, through which the virus binds to the cellular receptors at the surface of T-helper lymphocytes or CD4⁺ cells. The binding of virus to the CD4 receptor in association with chemokine co-receptor causes a dynamic change in gp120 and further activates trans-membrane protein gp41. These changes cause fusion of HIV envelope to the cell membrane of CD4⁺ cell and further make way for the entry of virus into the cytoplasm of CD4⁺ cell. The virus entry inhibitors sabotage the ability of gp41 to mediate fusion of viral and cellular envelopes. HIV entry inhibitor drugs are of first choice after exposure to virus and are newer drugs in the scenario of HIV therapy. Currently, most regimens of HIV therapy are combinations of inhibitors of two viral enzymes: reverse transcriptase and protease. HIV entry inhibitors are of great interest because of their activity against multi-drug resistant viruses.

The brief mechanism of HIV entry into T-helper lymphocytes or CD4⁺ cells has been cited above. The main receptors used by HIV-1 are chemokine receptors CCR5 and CXCR4. It has been resolved through the assessment of amino acid sequences of different HIV-1 strains that there are five variable (V1-V5) and four constant (C1-C4) regions in gp120. The expression of CCR5 or CXCR4 on the surface of CD4⁺ target cells (T-helper lymphocytes) defines their susceptibility to infection by corresponding HIV-1 strain. The use of specific receptors by viruses for infecting the target cells determines the virus cell tropism. The dual tropic viral strains can use both the receptors at the surface of CD4⁺ target cells. The HIV entry inhibitor compounds could be targeting the inhibition at different stages of virus entry such as:

1. The attachment inhibitor: Sulfated polysaccharides or polyanions such as dextran sulfate (dextran-2-sulfate or D2S) and heparin have been shown to inhibit binding of V3 loop antibodies to HIV-1 gp120 in-vitro.


2. Inhibitors of gp120-CD4 interaction: The currently available inhibitors of gp120-CD4 interaction are PRI 542 (CD4 - IgG2), TNX 355, and BMS 488043 antibodies/molecules. PRI 542 (CD4 - IgG2) is a tetravalent antibody and has passed clinical trials. TNX 355 is a monoclonal antibody (humanized) against the domain-2 of human CD4. BMS 488043 is a small molecule and blocks the entry of virus by preventing the binding of gp120 to CD4 receptors on CD4⁺ target cells.


3. Co-receptor Antagonists: Some new molecules have been tried as antagonists to CXCR4 and CCR5 but abandoned due to cardiac abnormalities and heart conduction abnormalities like prolonged QT intervals. CCR5 is the co-receptor mainly used by HIV for its transmission; so many drugs have been enlisted for targeting CCR5.

It is well established now that R5 viruses remain present in approximately 50-60% of individuals who progress to AIDS, whereas remaining 40-50% of individuals switch to X4 viruses with the progression of the disease and show a decline in the count of CD4⁺ target cells. The mutations in viruses confer them resistance to CCR5 treatment in the absence of co-receptor switch. HIV entry inhibitor compounds have been gaining importance as therapeutic agents for the treatment and post exposure prophylaxis against HIV.