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

      Hepatobiliary Dysfunction in HIV

      • Digestive system showing bile duct⁶

        Public Domain:  Digestive system diagram http://commons.wikimedia.org/wiki/File:Digestive_system_showing_bile_duct.png

      • HIV patients may be affected by gallbladder and biliary diseases.⁹ 

        • Some of these disorders are quite common such as non-HIV-associated cholelithiasis (lithiasis (stone fomration) in the galbladder)

          • Opened gall bladder containing gallstones⁷

            Emannuelm Opened gall bladder containing numerous gallstones Larger yellow calculus is likely due to cholesterol; green-to-brown stones indicate bile pigments including biliverdin and stercobilin. http://en.wikipedia.org/wiki/Gallstone http://commons.wikimedia.org/wiki/File:Gallstones.jpg

        • Common AIDS-associated conditions include acalculous cholecystitis and cholangiopathy.⁹ 

        • Such patients may exhibit postprandial discomfort (pain), fever, upper right quadrant pain and tenderness as well as elevated serum alkaline phosphatase.

          • Either ultrasonography or computed tomography (CT) imaging may reveal acute cholecystitis or cholangitis related to cholelithiasis.⁹ 

            • Ultrasound Image of a 1.9 cm Gallstone⁸

              Heilman J "A 1.9 cm gallstone impacted in the neck of the gallbladder and leading to cholecystitis. (Note the 4 mm bladder wall thickening.)" http://commons.wikimedia.org/wiki/File:Gallstones.PNG

          • In patients with advanced HIV disease, such findings may indicate acalculous cholecystitis or AIDS-associated cholangitis.^9,10

            • Should a cholecystectomy be performed in an HIV patient, specimens from the gallbladder should be sent to pathology for evaluation.¹¹  

              • Prior to the availability of cART (HAART) combined highly active antiretroviral drugs, opportunistic pathogens were found in the following study in >50% of cases.¹¹  

                • This clinical study that described these opportunistic pathogens in HIV patients was based on such patients undergoing cholecystectomy between February 1987 and May 1993.

                  • Pathogens described in this study of 107 AIDS patients included microsporidia (Enterocytozoon bienuesi and Septata intestinalis), Cryptosporidium, cytomegalovirus + Cryptosporidium, Pneumocystis jiroveci (PCP) and Isospora belli.¹¹ 

                  • Histologic changes consistent with Kaposi's sarcoma was also noted in one case.

                  • In 38 AIDS patients with acalculous cholecystitis, no etiologic agent was determined.

                    • Furthermore, 28 AIDS patients had cholelithiasis and some exhibited coexistent opportunistic gallbladder infection.¹¹ 

          • If cART combination anti-retroviral treatment is being administered the likelihood of AIDS cholangiopathy appears quite low, suggesting that this disorder might be seen in patients with CD4+ T cell counts of <50mm³.⁹ 

            • In the cART setting, noninfectious disease such as cholelithiasis likely accounts for the increased proportion of hepatobiliary disease in HIV patients.

              • One HIV protease inhibitor, atazanavir, may predispose the patient to biliary stone development and the stones are found to contain "significant concentration of the actual drug."⁹

          • Under the circumstances in which noninvasive radiographic imaging studies suggest intrahepatic/extrahepatic biliary ductal dilation, ERCP (endoscopic retrograde cholangiopancreatography) may be required for diagnosis and optimal management of AIDS-associated cholangiopathy.⁹

            • ERCP Diagram¹²

              Cancer Research UK, "Detailed diagram of an endoscopic retrograde cholangiopancreatography (ERCP)12 In the ERCP procedure an endoscope (flexible camera) is passed down the esophagus, through the stomach into the duodenum to the ampulla of Vater (opening of the common bile duct and pancreatic duct.  The anatomy iv viewed via the endoscopic camera.  A catheter is inserted through the ampulla and radiocontrast dye injected into bile and/or pancratic duct(s). Fluoroscopic imaging allows for identification of blockages, stones and other abnormalities.13

            •  

              Normal ERCP (Endoscopic Retrograde Cholangiopancreatography)¹⁶

              Attribution: Pohl J Normal Endoscopic Retrograde Cholangiopancreatography https://www.youtube.com/watch?v=h7gCWo1b7ZA Video Journal and Encyclopedia of GI Endoscopy YouTube Channel:  https://www.youtube.com/channel/UCi2dnUWyTDjO3uXrFX2gYTQ

           

          • Four distinctive patterns describing cholangiographic pathologies may be noted with ERCP.⁹  

            • These patterns include:

              • Papilla of Vater stenosis with associated dilated extrahepatic biliary tract

              • Sclerosing cholangitis

              • Sclerosing cholangitis + papillary stenosis

              • Choledochal long stenosis/strictures⁹  

            • Opportunistic pathogens or malignant diseases may be determined from endoscopic bile collection from the common bile duct along with duodenal or papillary biopsy.⁹ 

              • Cholangitis (similar to acalculous cholecystitis noted earlier) occurs with opportunistic infections > 50% of cases.

                • These infections include:

                  • CMV (cytomegalovirus)

                  • Cryptosporidium

                  • Microsporidia ⁹ 

                • Additional infectious pathogens that have been identified include Cryptococcus neoformans, Cystoisospora belli, and pneumocystis jiroveci.⁹ 

                  • Biliary tree malignancies that have been described include lymphoma and Kaposi's sarcoma.⁹

              • In one study undertaken as a result of a 1993 municipal water supply in Milwaukee, Wisconsin (USA) Cryptosporidia contamination with a resulting cryptosporidosis outbreak.¹⁵ 

                • The authors evaluated retrospectively associations among clinical presentation, CD4⁺ T cell count, and survival in a group of 82 patients who had been infected with HIV and who developed cryptosporidosis during this outbreak.

                • A clear increase in the number of HIV-infected patients with cryptosporidosis was noted following the period of water contamination.

                  • Some patients (four of 24) displayed biliary symptoms; however, 30 of 58 presented without biliary symptoms.¹⁵

                    • 4 of the 24 and 30 of the 58 remained alive one year following the outbreak. 21 patients (80%) with biliary symptoms exhibited CD4⁺ T cell counts ≤ 50/mm³. 36 of 57 (63%) without biliary symptoms had CD4⁺ T cell counts ≤ 50/mm³.

                    • The clinical study suggested that when HIV-infected patients are exposed to Cryptosporidium, and have CD4⁺ T cell counts ≤ 50/mm³, both an increased risk for biliary symptoms and death are found within one year after infection.¹⁵

                      •  

                        Cryptospordium Infection Survival among Patients with CD4 Counts ≤ 50 per Cubic Millimeter¹⁵

                        "Days refers to the number of days after the onset of symptoms (base line), and the symbols indicate deaths."15 Patients with CD4 counts above 50 per cubic millimeter had signficantly higher rates of survival than those with CD4 counts of 50 per cubic millimeter or less (6 deaths vs. 41 deaths)." 15

            •  

              ERCP: Fluoroscopic Common Bile Duct Imaging¹⁴

              Samir Fluoroscopic image of a commone bile duct stone visualized during ERCP. "The stone is impacted in the distal common bile duct." (2007)