Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiviral Drugs

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

    • HIV-1 Pathophysiology/Pathogenesis:  HIV Disease Presentations

      HIV Effects on the Gastrointestinal System (continued):

      • Protozoal Infections:

        •  Microsporidia²

          • Microsporidia are unicellular, intracellular parasites associated with enteric (gastrointestinal) cell cytoplasm.

            • In humans the main species resulting in disease is Enterocytozoon bienuesi.

            • Clinical presentation is comparable to that seen with cryptosporidia including:

              • Diarrhea

              • Abdominal pain

              • Malabsorption

              • Cholangitis

            • Diagnosis may utilize intestinal aspirate, intestinal biopsy or even electrom microscopic examination of stool.²  

          • Microsporidia has also been found in extraintestinal sites such as eye, brain, muscle, sinuses, and liver.

            • In the eye this parasite appears associated with conjunctivitis and in the liver appears associated with hepatitis.

            • In an example catchment group, from the Czech Republic, seropositivity for Enterocytozoon bienuesi was assessed.⁸ 

              • 115 serum samples from different groups were tested for seropositivity.⁸  

                • 20% of samples from HIV-positive individuals were positive for Enterocytozoon bienuesi .

                • About 33% of individuals with occupational exposure to animals tested positive and overall about 10% seropositivity was identified from healthy individuals.

                • The assessment method depended on an indirect immunofluorescence assay.⁸ 

          • Microsporidial infection in HIV patients may be most effectively managed by administration of cART (HAART) i.e., highly active combination anti-retroviral drugs.

      •  

        Microsporidiosis:  Microsporidia Life Cycle⁷

        "The infective form of microsporidia is the resistant spore and it can survive for long time in the environment (1). "The spore extrudes its polar tubule and infects the host cell (2). "The spore injects the infective sporoplasm into the eukaryotic host cell through the polar tubule (3). "Inside the cell, the sporoplasm undergoes extensive multiplication either by progeny (binary fission) or schizogony (multiple fission) (4). "This development can occur either in direct contact with the host cell cytoplasm (e.g., E. bienuesi) or inside a vacuole termed parasitophorous vacuoles (e.g., E. intestinalis). Either free in the cytoplasm or inside a parasitophorous vacuole, microsporidia develop by sporogony to mature spores (5). "During sporogony, a thick wall is formed around the spore, which provides resistance to adverse environmental conditions. When the spores increase in number and completely fill the host cell cytoplasm, the cell membrane is disrupted and releases the spores to the surroundings (6). "These free mature spores can infect new cells those continuing the cycle."

        DPDx-Laboratory Identification of Parasitic Disease of Public Health Concern:  Centers for Disease Control (CDC).  Microsporidiosis, Parasite Biology. http://www.cdc.gov/dpdx/microsporidiosis/ Above figure legend is quoted from http://www.cdc.gov/dpdx/microsporidiosis/

         

        •  Isospora belli:

          • Isospora belli, a coccidian parasite, is usually found as a cause of diarrhea in individuals from tropical and subtropical regions.² 

            • Isospora belli¹⁰

              Van den Enden, E Illustrated Lecture Notes on Tropical medicine:  HIV and AIDS-Opportunistic infections, treatment

            • Infection occurs as a result of oocyst ingestion.⁹ 

            • The parasite then invades intestinal epithelial cells and proceeds through development cycles.

            • In immunocompromised patients, including AIDS patients, Isospora belli infections may not be self-limited, instead resembling cryptosporidosis with chronic, watery diarrhea.

              • Eosinophilia, not found in other enteric protozoan infections, may be noted with I. belli.⁹ 

      • CMV Colitis

        • Colitis as a result of cytomegaloviral (CMV) infection had been observed in about 5%-10% of AIDS patients prior to the advent of cART (HAART) therapy.

          • Patients receiving contemporary combinations of anti-retroviral drugs are much less likely to experience CMV colitis.

            • CMV colitis is however associated with diarrhea, weight loss, abdominal pain and anorexia.

            • Diagnosis may be obtained through endoscopy and biopsy with endoscopy revealing multiple mucosal alterations and biopsies showing intra-nuclear and cytoplasmic inclusions. As a result of bowel wall thinning, secondary bacteremias may occur.

      • An algorithm for diagnosis and management of diarrhea in patients infected with HIV has been described:

        •  

          "Diagnosis and Management of HIV-Associated Diarrhea"11

          "Basic algorithm for the diagnosis and management of human immunodeficiency virus-associated diarrhea. Diarrhea was defined as the abnormal passage of loose or liquid stools ≥ 3 times a day, and/or a liquid stool volume of >200 g/d.. Upper endoscopy and colonoscopy should be strongly considered for patients with CD4+ cell counts <100 cells/µL. Abbreviations: HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus." MacArthur RD DuPont HL Etiology and Pharmacologic Management of Noninfectious Diarrhea in HIV-Infected Individuals in the Highly Active Antiretroviral Therapy Era (Reviews of Anti-infective Agents, Invited Article) Clinic Infectious Diseases 56(6):  860-867 2012. http://www.natap.org/2013/HIV/ClinInfectDis.-2012--860-7.pdf The figure above corresponds to Figure 1 in reference 11.