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

      Renal Dysfunction (continued)

      • Electrolyte abnormalities: (continued)

        • Hypokalemia⁵ 

          • Diarrhea

            • Diarrhea is perhaps the most common gastrointestinal complaint in HIV-infected patients.¹⁴

              • Bacterial causes include:¹⁴

                • Shigella

                • Salmonella

                • Enteroadherent Escherichia coli

                • Entamoeba histolytica

                • Campylobacter

                • M. avium intracellulare complex

                • Clostridium difficile and others.

              • Parasitic causes of diarrhea include:¹⁴

                • Giardia lamblia

                • Cryptosporidium

                • Isospora belli and others

              • Viral causes of diarrhea, in addition to HIV include:¹⁴

                •  CMV (cytomegalovirus)

                •  HSV (herpes simplex virus) and others.

              • Fungal causes of diarrhea include:¹⁴

                • H. capsulatum

                • C. neoformans and others.

            • Diarrhea is an established side effect of protease inhibitor agents typically used as part of cART (combination antiretroviral therapy) and includes agents such as nelfinavir and ratonavir.¹⁴ 

            • In patients with advanced HIV disease, the most common pathogens appear to be cytomegalovirus (CMV) and M. avium intracellulare complex.¹⁴

            • About 15% of individuals with late-stage AIDS experience severe, high-volume watery diarrhea for which the a pathogen-based cause is not established.

              •  In that case, AIDS-related enteropathy would be a diagnosis of exclusion.

            • Correction of electrolyte abnormalities and rehydration in this setting may require inpatient hospital management.¹⁴ 

              • Octreotide, a somatostatin related agent, may be useful.

              • Initial management of HIV-related diarrhea would include replacement of lost fluid and electrolyte normalization.

              • For those patients exhibiting severe diarrhea but not requiring antibiotics symptomatic therapy may be appropriate.

                • Such therapy might include attpulgite (Kaopectate), psyllium (Metamucil) as well as diphenoxylate + atropine (Lomotil).¹⁴

          • Fanconi Syndrome:

            • Fanconi syndrome is a tubular pathology which causes excess urinary excretion of glucose, bicarbonate, uric acid, phosphates, potassium, some amino acids and sodium.¹⁵

            • Fanconi syndrome may be either inherited or acquired and in the HIV-positive population, the syndrome can develop as a result of administration of certain antiretroviral drugs.¹⁶ 

              • In one case study, a patient with Fanconi syndrome (as well as nephrogenic diabetes insipidus) exhibited hypophosphatemia, hypouricemia, hyperchloremic metabolic acidosis with normal anion gap, normoglycemic glycosuria as well as low-molecular-weight protein-uria.¹⁶ 

              • This patient was ultimately diagnosed with didanosine-associated Fanconi syndrome and administration of that drug was discontinued.

                • However, other drugs part of the patient's antiretroviral regimen, lamivudine, atazanavir, and ratonavir were continued.

                • One month following withdrawal of didanosine, glycosuria, tubular proteinuria, metabolic acidosis and hypernatremia had resolved.

                  • At that point, a second protease inhibitor was added to the antiretroviral treatment protocol.¹⁶

              • Another case report has identified tenofovir, a nucleotide reverse transcriptase inhibitor, as causative of acquired Fanconi syndrome in an HIV positive individual.¹⁷ 

                • In the patient described in the case study, Fanconi syndrome was suggested due to hyperchloremic nonanion gap metabolic acidosis, hypokalemia, hypophosphatemia, glucosuria and proteinuria.

                • Tenofovir administration was discontinued and the patient rehydrated.

                  • Rehydration required potassium chloride replacement twice daily for two days in order to maintain potassium above 3 mEq/L for the first five days of hospitalization.¹⁷ 

                    • Resolution of symptoms followed.

                    • Other drugs besides tenofovir have also been implicated in acquired Fanconi syndrome.

                      • These drugs include aminoglycosides, ifosfamide, cisplatin, streptozocin, mercaptopurine, tetracycline, adeforvir, and valproic acid.^5,17

        • Hypercalcemia⁵

          • Hypercalcemia has been identified in a relatively small percentage of AIDS patients (about 3% in a 66 patient study).¹⁸ 

            • In HIV-positive individuals hypercalcemia may be a consequence of infection, granulomatous or neoplastic disease, or a drug side effect.¹⁸  

              • Infections which may become associated with hypercalcemia in HIV-infected individuals include opportunistic pathogens discussed earlier such as:¹⁸

                • Cytomegalovirus (CMV)^18,19,20

                  • Hypercalcemia secondary to CMV infection may be due to direct osteoclastic activation by activated T cells or proinflammatory cytokines.

                • Pneumocystis jirovecii (PCP, formerly pneumocystis carinii)

                • Mycobacterium avium intracellulare

                • Cryptococcus neoformans

                • Coccidioides immitis.

              • Hypercalcemia may also occur in protozoal, fungal and mycobacterial infection and in the circumstances may occur due to extrarenal 1α-hydroxylation of 25-hydroxy-vitamin D₃ by macrophages, epithelioid cells, monocytes and multinucleated giant cells.¹⁸ 

                • This mechanism has been suggested in patients who present with AIDS-associate lymphoma and hypercalcemia.¹⁸

              • Forcarnet is an example of a drug which may cause hypercalcemia in  HIV patients.^18,21

                • Pentamidine is another example.⁵

              • Non-Hodgkin's lymphoma is an example of a neoplasm which may be associated with hypercalcemia in HIV patients.^18,22,23

        • Hypocalcemia⁵

          • Hypocalcemia has been found associated with HIV infection.²⁴ 

            • HIV positive individuals may exhibit reduced 1,25-hydroxyvitamin D and 25-hydroxyvitamin D levels with normal vitamin D-binding protein levels.

              • This finding indicates both abnormalities in 1-α hydroxylation and nutritional state.

            • Reduced 1,25-hydroxyvitamin D levels are more likely found in advanced HIV disease along with increased TNF-α levels (TNF: Tumor Necrosis Factor).

            • Reduced parathyroid hormone responses (PTH responses), an effective functional hypoparathyroidism, may also predispose to HIV-related hypocalcemia.

              • Parathyroid cells may be infected by HIV-1 virus as the cells express the CD4 HIV receptor.

                • Furthermore, activation of CD4 receptors influence PTH secretion.

            • More serious hypocalcemia in the HIV setting is more likely related to medications used to manage opportunistic infections.²⁴ 

              • Both hypocalcemia and hypophosphatemia appear associated with the HIV antiviral agents tenofovir and adefovir.

              • Foscarnet, used for management of CMV retinitis, appears also associated with reduced calcium levels.

                • Foscarnet and ionized calcium may form a complex that results in "mineral wasting effects" at the renal tubules which results in hypomagnesemia and hypokalemia.

              • Pentamidine administration may cause both hypocalcemia and hypomagnesemia.

                • Additionally, the combination of pentamidine and foscarnet may result in a severe, potentially fatal, hypocalcemia.

              • Hypocalcemia may also occur following administration of trimethoprim-sulfamethoxazole, ketoconazole, and aminoglycoside drugs.²⁴

        • Other Electrolyte Effects⁵ :

          • Hypomagnesemia

          • Metabolic Acidosis

          • Fanconi Syndrome