Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiviral Drugs

  • Anti-viral drugs with activity against HIV (Human Immunodeficiency Virus)

    • Viral Transmission²

      • "HIV Transmission and Pathogenesis"¹⁵

        Attribution: Lahey T, MD, Geisel School of Medicine Dartmouth,  HIV Transmission and Pathogenesis https://www.youtube.com/watch?v=mErbBxoTJDw (2/2013) UndergroudMed YouTube Channel https://www.youtube.com/channel/UClFTJ35LhEhNuwPynuGo_PA

      • HIV is mainly transmitted by sexual contact (both heterosexual and male to male); by blood and blood products and by infected mothers to infants (intrapartum, perinatally or by means of breast milk). No evidence exists suggesting that HIV may be transmitted by casual contact or that the virus can be spread by insects (e.g. mosquito bite).²

      • Sexual transmission:^2,8

        • HIV infection is mainly an STD (sexually transmitted disease) worldwide.

          • The most common infection mode, especially in developing countries, is heterosexual transmission.

          •  In many Western countries, an increase in incidence of male-to-male sexual transmission has developed.

            • The likelihood of heterosexual HIV transmission is influenced by viral load as well as by presence of ulcerative genital diseases; however heterosexual transmission is usually inefficient.

          • A major study considered 174 monogamous couples in which one partner was HIV-1 positive.

            • The study involved a population in Rakai, Uganda.

            • Intercourse frequency and reporting reliability within couples were evaluated prospectively.

              • HIV-1 seroconversion was determined in uninfected partners.

              • HIV-1 viral load was measured in infected partners. Rates of HIV-1 transmission per coital was determined.

            • The study reported that the mean intercourse frequency was 8.9 per month, declining both with age and HIV-1 viral load.

            • Members of couples reported comparable intercourse frequencies.

              • The overall unadjusted likelihood of HIV-1 transmission per coital act was 0.0011 i.e. about 0.11%.

              • The transmission likelihood increased from about 0.01% per act and viral loads less than 1700 viral copies/ml to 0.23% per coital act at 38,500 copies/ml or more.

              • A higher likelihood of transmission per coital act was noted if genital ulcer disease was present in the HIV-1 positive partner (0.41% vs 0.11%.)

                •  

                  Probability of HIV transmission per coital act^2,8

                  "Probability of HIV transmission per coital act (among monogamous, hetersexual, HIV-serodiscordant couples in Uganda)." Attribution:  This figure corresponds to Figure 189-9 of reference 2 and is based on data from reference 8.

                •  

                  "Levels of CD₄T cells and HIV RNA in blood during HIV Infection"¹⁴

                  "The concentration of HIV RNA is a measure of viremia. "Shortly after infection viremia rises, then it falls off and relatively low levels are detectable throughout the asymptomatic period.  "A rise in viremia heralds the onset of AIDS."14 Figure attribution: Carter JB Saunders VA Virology: Principles and Applications Chapter 18, Figure 18.13 John Wiley & Sons Ltd, 2013.14

          • The presence of HIV in seminal fluids within infected mononuclear cells and in cell-free material has been shown.² 

            • Viral concentration in the seminal fluid appears enhanced under circumstances associated with increased lymphocyte and monocyte number in the fluid.

              • Urethritis and epididymitis, seen with other sexually transmitted diseases as well, represent such circumstances.² 

            • An increased risk of HIV transmission has been associated with unprotected receptive anal intercourse (URAI), affecting both men and women when compared to the risk associated with receptive vaginal intercourse.² 

              • A tentative estimate of the "per-act" risk for HIV transmission associated with URAI is about 1.5% for men and women (review/meta-analysis).² 

                • HIV acquisition risk due to URAI is likely higher than that seen in penile-vaginal intercourse as a result of a thin, fragile rectal mucosal membrane, separating deposited semen from susceptible cells in and beneath the mucosa.

                  • Another factor may be the trauma of anal intercourse.

                  • Anal douching and sexual practices which traumatize the rectal mucosa increase the infection probability.

                  • Anal intercourse may be associated with at least two infection modalities.

                    • (1) Inoculation into blood, directly, because of mucosal traumatic tears.

                    • (2) Presence of susceptible target cells, including Langerhans cells, in the mucosal layer.

                      •  

                        HIV Crossing Mucosal Epithelium⁹

                        "Possible routes by which HIV may cross mucosal epithlium during sexual transmission." LCs = Langerhans cells.

                      •  

                        HIV-1 Interactions with Langerhans Cells¹⁰

                        "HIV1 was captured by Langerin expressed by LCs and MUTZ3/LCs(arrows) and internalized into Birbeck granules (arrowheads)."10 Figure Attribution:  The above figure corresponds to Figure 2 (C):  Langerin is the HIV-1 receptor on immature LCs, reference 10. de Witte L Nabatov A Pion M Fluitsma D de Jong MAWP de Gruijl T Piguet V van Kooyk Y Feijtenbeek TBH Nature Medicine 13: 367-371 (2007) Published online: 4 March 2007.

                  • Despite the vaginal mucosal structure being several layers thicker than rectal mucosa and accordingly more resistant to being traumatized during intercourse, the HIV-1 virus may be transmitted to either partner during vaginal intercourse.

                  • Clinical studies suggest that male-to female HIV transmission is likely more efficient than female-to-male transmission.

                    • Such differences may be due to longer seminal fluid vaginal-cervical mucosal exposure.

                      • On the other hand, the penis and urethral orifice are exposed only briefly to infected vaginal fluid.² 

                • Cofactors which have been examined as possibly affecting heterosexual HIV transmission include concurrent infection with other STDs.² 

                  • This cofactor appears strongly associated with HIV transmission.

                  • As suggested earlier, a close association between genital ulcerations and transmission has been identified.

                    • This association may be due both to susceptibility to infection and infectivity.

                    • Causes of genital ulcerations associated with HIV transmission include infections with Treponoma pallidum, Haemophilus ducreyi, and herpes simplex virus (HSV).²

                    •  

                      Treponoma pallidum¹¹

                      CDC/ Dr. David Cox Electron micrograph of Treponema pallidum on cultures of cotton-tail rabbit epithelium cells (Sf1Ep). Treponema pallidum is the causative agent of syphilis.11 http://commons.wikimedia.org/wiki/File:Treponema_pallidum.jpg

                    •  

                      Haemophilus ducreyi¹²

                      CDC (CDC Public Health Image Library, Haemophilus ducreyi bacteria-causative agent of chancroid.12	"A rabbit blood culture photomicrograph of Haemophilus ducreyi bacteria using Gram-stain technique.13 "H. ducreyi is the primary cause for a condition know as “Human Genital Ulcer Disease” or “Chancroid”, especially in developing countries. The transmission of this bacterium and HIV has been epidemiologically linked."13 Attribution:  CDC (CDC Public Health Image Library.13

                       

                  • Other pathogens that cause nonulcerative inflammatory sexually transmitted diseases are also associated with elevated HIV transmission infection risk.

                    • Examples of these pathogens include:

                      • Chlamydia trachomatis

                        • Chlamydia trachomatis¹⁶

                          Liotta L Human pap smear depicting clamydia in the vacuoles at 500x; H&E stain16 March  1988, public domain, NCI Visuals online https://visualsonline.cancer.gov/details.cfm?imageid=2331

                      • Neisseria gonorrhoeae

                        • Neisseria gonorrhoeae¹⁷

                          Fankhauser DB Bacteria on Prepared Slides:  Neisseria. "This is a Gram stained smear of a purulent urethral discharge. "Large number of polymorphonucleocytes are present with a few squamous cells. "In the cytoplasm of the PMNs* can be see phagocytosed GM-diplococci which are indicative of gonorrheal infection." *polymorphonuclear leukocytes

                      • Trichomonas vaginalis

                        •  

                          Trichomonas vaginalis¹⁸

                          Brollo A Pap test, Papnicolau stain, 400x Infestation by Trichomonas vaginalis.

        • Oral Sex:²

          • Oral sex is considered a significantly less efficient transmission mode of HIV compared to anal intercourse or vaginal intercourse.

            • Given reports of documented HIV transmission as a result of oral sex, any assumption that oral sex is completely safe is not supported.²

        • HIV transmission risk and drug use:²

          • HIV transmission risk appears also increased when associated with alcohol consumption, illicit drug use combined with unsafe heterosexual and homosexual behavior.

            • Taking certain drugs such as methamphetamine as well as other "so-called club drugs"-e.g., ecstasy, ketamine, gamma hydroxybutyrate, possibly in conjunction with phosphodiesterase-5 inhibitors (e.g. sildenafil (Viagra), tadalafil (Cialis) or vardenafil (Levitra) appears associated with risky sexual practices and attendant elevated HIV infection risk (particularly in male-to-male sex).²