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

      • Kidney disease may occur as a:

        • Direct result of infection with HIV²

          • HIV-1 has been demonstrated in clinical and animal studies to infect renal parenchymal cells in HIVAN (HIV-associated neuropathy).⁵ 

            • HIV DNA and mRNA have been demonstrated in human renal tissue. Local renal viral replication has been shown.

              • An HIV viral reservoir may include renal epithelium.

              • HIV appears to enter renal epithelial cells without depending on CD4⁺ or other currently identified HIV coreceptors.

                • One study involving T cells fluorescently labeled with HIV virus and exposed to renal tubular epithelial cells found direct viral intercellular transfer.

                • Such transfer did not require CD4⁺ but was dependent on cell-cell adhesion.

                  • Following viral internalization, HIV-specific proteins were synthesized.⁵ 

            • Although evidence that HIV1 might infect kidney cells in HIVAN, definitive data supporting renal epithelial cell HIV-1 infection was presented in 2000.⁹ 

              • Early on, patients with HIV disease affecting the kidney exhibited rapid progression to end-stage renal disease and death.

                • However, more attention was focused on AIDS-defining opportunistic infections along with malignancies during the first decade of the HIV epidemic.⁹ 

              • In 2000, investigators utilized three methods which confirmed HIV-1 in human kidney tissue.¹⁰ 

                • These methods included:

                  • PCR (polymerase chain reaction) for circularized episomal cDNA

                  • mRNA in situ hybridization involving two riboprobes capable of detecting spliced or full-length viral mRNA

                    • "in situ Hydridization for HIV-1 mRNA in kidney Biopsies"^9,10

                      "(A and B):  Kidney biopsy from an HIV-negative patient demonstrating no HIV-1 mRNA in the sense control (A) or the antisense (B) hybridization of a serial section. "(C and D):  Kidney biopsy from an HIV-positive patient with kidney disease.  No hybridization was observed in the sense control (C). "Antisense hybridization (D) demonstrates HIV-1 mRNA in the cytoplasm of tubular epithelial cells and in cellular casts (CC) in the tubular lumen (TL) but not in the protein casts (PC). "Magnifications:  x125 in A and B; x60 in C and D."9,10 Figure above corresponds to Figure 1 in reference 9 and in Figure 5 in the original paper, reference 10.

                  • DNA in situ PCR.

              • HIV-1 RNA (nef and gag) and DNA (env) were detected in HIV-1 renal epithelial cells.

                • Such detection was possible even in patients showing "undetectable"(i.e. <50 copies/ml) levels of viral RNA in peripheral blood.

                  • Active replication (suggested by the presence of extrachromosomal circular DNA in leukocytes or renal epithelial cells) continued in patients with undetectable viral burdens, a finding consistent with the kidney harboring replicating virus.

        • Indirectly as a result of opportunistic infection or neoplasm.² 

          • Furthermore, drug toxicity may also result in renal dysfunction.² 

      • Microalbuminuria is noted in about 20% of untreated HIV-infected individuals and significant proteinuria is seen in about 2% of untreated HIV patients.² 

        • Microalbuminuria appears indicative of an increased mortality rate, due to all causes. 

        • HIV-associated neuropathy (HIVAN) has been identified as a direct HIV-infection complication and may be noted as an early indicator of HIV infection.² 

          • HIV-associated neuropathy (HIVAN)⁶

            (A, left image):  "HIV-associated nephropathy (HIVAN) with collapsed glomerulli, characteristic microcystic transformation of renal tubules, and concomitant interstitial inflammation and fibrosis." (B, right image):  "High-power view of collapsing glomerulopathy in a case of HIVAN with collapse of glomerular capillary structures and striking hyperplassia of podocytes." "Magnifications:  x100 in A; x400 in B (Jones methenamine silver stain in both." http://cjasn.asnjournals.org/content/2/Supplement_1/S6/F1.expansion (2015)

          •  

            "Tubuloreticular Structures in Glomerular Endothelial Cells"⁸

            "The electron microscopy image was acquired from a renal biopsy specimen of a patient \with HIV-associated nephropathy (HIVAN), original magnification x16000" (Dikman S, Department of Pathology, Mt Sinai Hospital, New York, NY, USA). Image corresponds to Figure 2 in reference 8. Anders H-J Lichtnekert J Allam R Interferon-α and -β in kidney inflammation.  Mini-Review:  Kidney International 77:  848-854, 2010. http://www.nature.com/ki/journal/v77/n10/full/ki201071a.html

          • Most of the time, however, HIV-associated neuropathy (HIVAN) is found in patients who exhibit a CD4⁺ T cell counts of <200/µL.

            • HIVAN may also occur in children.²

          • The majority of  HIVAN cases, >90%, occur in African-American or Hispanic patients and is a more severe in this population.²

            •  HIVAN has been described as the third leading cause of end-stage renal failure in the African-American 20-64 age group.

              • Proteinuria is considered the prominent indication of HIVAN with the definitive diagnosis requiring renal biopsy.^2,5 

                • Focal segmental glomerulosclerosis is typically present upon histological examination.² 

          • cART administration (HAART, highly active antiretroviral treatment) seems to decrease the rate of progression to end-stage renal disease.^2,5

            • Also, individuals with HIVAN should be treated for HIV infection independent of specific CD4⁺ T cell levels.

            • Other agents which may be beneficial include ACE inhibitors (angiotensin-converting enzyme inhibitors) and/or prednisone.^2,5