Table of Contents
I. Introduction
• The four decades of studying HIV
• The progress in making HIV manageable
II. Screening Landscape
• Introduction of 4th generation screening test
• Window period of different screening tests
• Confirmatory tests for HIV
III. Treatment Landscape
• Multiclass combination products
• Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
• Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
• Protease Inhibitors (PIs)
• Fusion Inhibitors
• Entry Inhibitors – CCR5 co-receptor antagonist
• HIV integrase strand transfer inhibitors
• Pre-Exposure Prophylaxis (PrEP)
IV. Conclusion
By 2020, the scientific community would have spent four decades of studying Human Immunodeficiency Virus (HIV). It is essential to accept and appreciate the scientific community that has worked tirelessly to make HIV as a manageable illness. HIV/AIDS, surrounded by myths and unwarranted fears, absorbed a lot of attention from both the media and the scientific community. From being conceived as a gay man’s disease, HIV had it all through the epidemic in the 1980s. It took extensive efforts from both regulators and researchers to debunk all the myths surrounding the infection in the last four decades. The rapid progress occurring in respect to screening techniques and treatment options continues to be a source of confusion even among some medical practitioners. Outdated information available on the internet only adds to more confusion. In the last two decades, as evidenced by numbers from UNAIDS, the new infection rates have come down by almost half from 3.2 million new cases every year to 1.8 new million cases in 2017. In combating HIV/AIDS, both screening tests and treatment options play an important role. Mybiosource Blog takes pride in presenting the most accurate/updated information related to screening and treatment options in this series of articles related to Human Immunodeficiency Virus (HIV).
Screening Landscape
The 4th generation screening test was introduced in the early 90s and the test screens for both antigens and antibodies related to HIV. Referred as p24 antigen tests, or combined antibody/antigen tests, the assay is efficient just after two to three weeks of exposure. The third-generation antibody tests have an average window period of 25 days, On the other hand, the average window period for p24 antigen tests is only 16 days. Only nucleic acid tests have lesser window period compared with p24 antigen tests. However, despite higher sensitivity and specificity, nucleic acids tests are not often used as frontline screening tests as its costly and almost impossible for mass usage. Therefore, along with western blotting, nucleic acid tests are used as confirmatory tests for HIV in laboratory settings. The Centres for Disease Control and Prevention (CDC) has set a waiting period, or a window period of 45 days for p24 antigen tests approved by the food and drug administration (FDA). For other tests, the CDC recommends a window period of 90 days, i.e., results are conclusive only after 90 days. Western blotting, Indirect fluorescent Antibody tests, and RNA tests are mostly seen as confirmatory tests. These tests are not only expensive but also would require technical expertise to carry out the assay. While Western blotting and Indirect fluorescent antibody tests are focused on detecting HIV antibodies, RNA tests (also referred as nucleic acid tests) are focused on identifying the genetic material of the virus.
Treatment Landscape
The treatment landscape also has seen significant changes in the last four decades. The FDA site, updated on April 12, 2018, shows seven major classes of drugs used in the treatment of HIV infection.
- Multiclass combination products
Combination of drugs from two different drug classes to inhibit viral replication in the human body are referred to as multiclass combination products. Combination products, though it offers the convenience of a single tablet per day, is not for everyone and is usually prescribed for people who start HIV treatment. For more about Multiclass combination products.
- Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Also known as Nucleoside analogs, NRTIs are the class of drugs that prevents/blocks reverse transcriptase from making copies of HIV. First approved in 1987, nearly 13 NRTI drugs are available in the market for treating HIV. For more about Nucleoside Reverse Transcriptase Inhibitors (NRTIs).
- Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Also known as non-nukes, NNRTIs blocks RNA from converting into DNA by attaching themselves to reverse transcriptase enzyme. As a result, HIV’s genetic material is not incorporated into host cell’s genetic material, thereby preventing viral replication. For more about Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs).
- Protease Inhibitors (PIs)
Class of drugs that act on the viral enzyme protease responsible for assembling new virus particles. Blocking the activity of protease slows production and release of new viral particles that infect immune cells. For more about Protease Inhibitors.
- Fusion Inhibitors
Class of antivirals, when taken in combination with other antivirals, slows down the replication of HIV within the human body. Currently, enfuvirtide (also known as T-20) is the only FDA approved Fusion Inhibitor available in the market. For more about Fusion Inhibitors.
- Entry Inhibitors – CCR5 co-receptor antagonist
CCR5 co-receptor antagonist is the newest class of antiretroviral drugs approved for HIV treatment and acts by inhibiting the HIV protein integrase from inserting the viral DNA genome into the host cell’s chromatin. For more about CCR5 co-receptor antagonist.
- HIV integrase strand transfer inhibitors
The FDA approved three new drugs under this latest class of antiretroviral since 2010: dolutegravir, elvitegravir, and raltegravir. These drugs inhibit/blocks the HIV protein integrase from aiding in the insertion of the viral DNA genome into the host cell’s chromatin. For more about HIV integrase strand transfer inhibitors.
- Pre-Exposure Prophylaxis (PrEP)
Recommended for High-risk population, PrEP has shown to reduce the risk of HIV infection by 92%. When exposed to HIV through injection or sex, these medicines help in keeping the virus from taking hold of host cells permanently. For effectiveness, PrEP must be taken on a timely manner as suggested by medical practitioners. For more about PrEP.
On the Horizon: Potential Antiviral Target Sites Based on the HIV life cycle, researchers have identified potential target sites for antivirals. As presented in the paper, “Pathogenesis and Treatment of HIV Infection: The Cellular, the Immune System and the Neuroendocrine Systems Perspective.” The target sites/pathways that are useful for exploitation are as follows:
- blocking of CD4 as the major HIV-1 cell receptor
- blocking of CCR5 co-receptor for the macrophage-tropic viruses and CXCR4 co-receptor for the T lymphocyte–tropic viruses
- blocking of RT
- blocking of integrase
- blocking of Tat-induced transcription of 9 kb RNA
- blocking of the Rev-dependent export of 4 and 9 kb transcripts to the cytoplasm
- blocking of viral protease and, as a consequence, virus maturation
- blocking of the Vpu-dependent inhibition of CD4 binding to gp160
- blocking of the Vif-dependent inhibition of APOBEC3G function
- blocking of the Nef-dependent endocytosis of class I MHC molecules and CD4
- blocking of the SAMHD1 mediated dNTPs degradation
- TRIM5 α mediated inhibition of infection at post-entry stage
- blocking of the Tetherin mediated inhibition of the virus release.
References: NCBI/Pubmed Comparison of 4th-Generation HIV Antigen/Antibody Combination Assay With 3rd-Generation HIV Antibody Assays for the Occurrence of False-Positive and False-Negative Results. https://www.ncbi.nlm.nih.gov/pubmed/25918186 Contribution of Combined Detection Assays of p24 Antigen and Anti-Human Immunodeficiency Virus (HIV) Antibodies in Diagnosis of Primary HIV Infection by Routine Testing https://www.ncbi.nlm.nih.gov/pmc/articles/PMC86847/ Fourth-Generation Enzyme-Linked Immunosorbent Assay for the Simultaneous Detection of Human Immunodeficiency Virus Antigen and Antibody. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC88179/