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.