Hiv Epid.docx

Regimen A 28-day course of nPEP is recommended for HIV-uninfected persons who seek care ≤ 72 hours after a nonoccupational exposure to blood, genital secretions, or other potentially infected body fluids of persons known to be HIV infected or of unknown HIV status when that exposure represents a substantial risk for HIV acquisition. Since adherence is critical for nPEP efficacy, it is preferable to select regimens that minimize side effects, number of doses per day and the number of pills per dose.1 The recommendation for a 3-drug antiretroviral regimen is based on extrapolation of data demonstrating that the maximal suppression of viral replication occurs among persons with HIV infection when combination antiretroviral therapy with ≥3 drugs is provided. Also, the likelihood of protection against acquiring resistant virus would be greater with a 3-drug regimen compared with a 2-drug regimen. Recommending a 3-drug regimen for all patients who receive nPEP will increase the likelihood of successful prophylaxis in light of potential exposure to virus with resistance mutation(s) and will provide consistency across PEP guidelines for both nPEP and PEP. 2 Additionally, if infection occurs despite nPEP, a 3-drug regimen will more likely limit emergence of resistance than a 2-drug regimen.1

Epidemiology Investigators from the Centers for Disease Control and Prevention (CDC) estimate that more than 380,000 total percutaneous exposures occur each year. Underreporting of exposures has long been recognized as a significant problem due to the perception of technical incompetence, nature of the intervention, lack of understanding of the risks, and concern about excessive paperwork. Despite a large number of reported exposures, the number of occupationally acquired HIV infections among healthcare workers (HCW) reported to the CDC has been much lower. Between 1985 and 2013, 58 confirmed and 150 possible cases of occupationally acquired HIV infections were reported to the CDC. Only one confirmed case has been reported since 1999. This case involved a laboratory technician working with a live HIV culture in 2008. Nurses accounted for the highest number of confirmed and possible occupationally acquired HIV cases, representing 41.4% and 24.7% of cases, respectively. 2 In 2016, Indonesia had 48,000 (43,000 – 52,000) new HIV infections and 38,000 (34,000 – 43,000) AIDS related deaths. There were 620,000 people living with HIV in 2016, among whom 13% were accessing antiretroviral therapy. Populations most affected by HIV in Indonesia are: Sex workers (5.3%), Gay men (25.8%), People who inject drugs

(28.76%). Transgender people (24.8%), and Prisoners (2.6%). Since 2010, new HIV infections have decreased by 22 % and AIDS-related deaths have increased by 68%.3 Pathogenesis HIV is an RNA virus whose hallmark is the reverse transcription of its genomic RNA to DNA by the enzyme reverse transcriptase. The replication cycle of HIV begins with binding of the gp120 protein to its receptor on the host of cell surface, the CD4 molecule. The CD4 molecule is a protein found predominantly on a subset of T lymphocytes that are responsible for helper function in the immune system. It is also expressed on the surface of monocytes/macrophages and dendritic/Langerhans cells. Once it binds to CD4, the gp120 protein undergoes a conformational change that facilitates binding to one of two major coreceptors. The two major co-receptors for HIV-1 are CCR5 and CXCR4. Certain dendritic cells also express receptors on their surface that also bind with gp120 envelope protein, allowing DC to spread virus to CD4+ T cells. Following binding of gp120 to CD4 molecule and the conformational change in the viral envelope, fusion with the host cell membrane occurs via gp41 molecule penetrating the plasma membrane of the target cell and then coiling upon itself to bring the virion and target cell together. Following fusion, uncoating of the capsid protein shell is initiated. As the preintegration complex transverses the cytoplasm to reach the nucleus, the viral reverse transcriptase enzyme catalyzes the reverse transcription of the genomic RNA into DNA, resulting in the formation of double stranded proviral HIV-DNA. With activation of the cell, the viral DNA accesses the nuclear pore and is exported from the cytoplasm to the nucleus, where it is integrated into the host cell chromosomes through the action of another virally encoded enzyme, integrase. HIV provirus (DNA) integrates into the nuclear DNA and this provirus may remain inactive or manifest varying levels of gene expression, up to active production of virus. Activation of HIV expression from the latent state depends on the interaction of a number of cellular and viral factors. Following transcription, HIV mRNA is translated into proteins that undergo modification through glycosylation, myristoylation, phosphorylation,

and cleavage. The viral particle is formed by the assembly of HIV proteins, enzymes, and genomic RNA at the plasma membrane of the cells. CD4+ T cell loss in individuals infected with HIV-1 occurs through direct infection of the CD4+ T cells and through indirect effects resulting from immune activation and apoptosis. Loss of CD4+ T cells is particularly striking during acute and early HIV-1 infection. Particular viral proteins and cytokines are toxic to CD4+ T cells, and some CD8+ T cells uninfected CD4+ T cells. In addition, the virus might inhibit thymic regeneration of CD4+ T cell numbers, thereby limiting recovery of CD4+ T cells in the infected host. The clinical manifestation of infection with HIV-1 results from the destruction of CD4+ T cells to the point where unusual infectious agents are able to take hold, leading to the “opportunistic” infections that characterize AIDS. Some people tolerate infection with the virus for long periods of time without health consequences. Long-term survivors, also known as long-term nonprogressors (LTNPs), maintain normal CD4+ T cell counts and low viral load in the absence of antiretroviral therapy. Innate and adaptive immunity have central importance in virus control and have both humoral and cellular immune activities. The primary difference between the innate and adaptive immune system is the quick response of innate immunity to a pathogen. The innate immune system recognizes conformational patterns of pathogens rather than specific epitopes. Soluble factors involved in innate immune responses include mannose-binding lectins and complement, both of which can inactivate HIV-1 directly. Among the cellular immune participants are DCs, NK cells, and a special subset of CD8+ T cells. DCs play a role in both innate and adaptive immunity. Various DC types found throughout the body have the major function of presenting antigen to T cells and B cells, resulting in adaptive immune responses. NK cells have an important role in destroying HIV-1–infected cells, and their function depends on efficient production of cytokines such as IL-12 and type 1 IFNs. CD8+ T cells have been identified that also participate in innate responses. They show anti– HIV-1 activity without killing the infected cell. This CD8+ T cell noncytotoxic antiviral response is mediated by a novel, but undefined, CD8+ T cell antiviral factor known as CAF

that blocks viral transcription. Such responses are highest in LTNPs, and a decrease in these responses leads to HIV-1 replication and disease progression. Antibody production is the primary humoral antimicrobial immune response of adaptive immunity and seems to be most important during the early stages of infection with most microbes. Antibodies that can neutralize HIV-1 virions are directed at various regions on the HIV envelope glycoproteins gp120 and gp41. Genetic and nongenetic factors influence viral sensitivity to neutralization; these include the expression of linear and conformational epitopes, the degree of envelope glycosylation, envelope stability, and whether cellular proteins become attached to the virion surface at the time of budding. Other antibodies that can have a beneficial effect are those that attach to virus-infected cells and induce direct cytotoxic responses of neutrophils and NK cells. Antibody-directed cellular cytotoxicity (ADCC) has been identified in some LTNPs and healthy infected individuals. However, some antibodies can bring HIV-1 into T cells and macrophages via the Fc or complement receptor and enhance infection; antibodies with these properties have been found in individuals who advance to AIDS. Following infection with HIV-1, presentation of antigens by DCs leads to the development of HIV-1–specific CD4+ T cells. These cells can sometimes have cytotoxic activity but primarily help in the development of HIV-1–specific CD8+ T cells and B cells that produce HIV-1–specific antibodies. Activated CD4+ T cells are more susceptible to infection with HIV-1 than other CD4+T cells in the infected host, so destruction of these CD4+ T cells early in infection might cause a lack of immune control of the HIV-1 infection. CD8+ T cell cytotoxic activities are associated with the control of many viral infections. This places an emphasis on HIV-1–specific CTL responses in preventing infection and advancement to disease. AIDS patients have HIV-1–specific CTLs, and some of these CTLs can be detrimental by lysing uninfected “bystander” CD4+ T cells and DCs. Importantly, HIV-1–specific CTLs might not be able to kill virus-infected cells because they lack perforin or other cytotoxic proteins. Moreover, HIV-1 has several mechanisms to resist HIV-1–specific CTLs; for example, mutations arise in viral antigenic peptides; DCs

express nonimmunogenic viral peptides; and HIV-1–infected APCs exhibit defects in antigen presentation.4

Referensi 1. Updated Guidelines for Antiretroviral Postexposure Prophylaxis After Sexual, Injection Drug Use, or Other Nonoccupational Exposure to HIV— United States, 2016. 2. Postexposure HIV Prophylaxis in Physicians and Medical Personnel: Practice Essentials, Epidemiology, Modes of Transmission [Internet]. [cited 2019 Feb 24]. Available from: https://emedicine.medscape.com/article/1991375overview#a8 3. Indonesia [Internet]. [cited 2019 Feb 20]. Available from: http://www.unaids.org/en/regionscountries/countries/indonesia 4. Cohen MS, Hellmann N, Levy JA, DeCock K, Lange J. The spread, treatment, and prevention of HIV-1: evolution of a global pandemic. J Clin Invest. 2008 Apr 1;118(4):1244–54.