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Resolution of Kaposi’s sarcoma associated with undetectable level of human herpesvirus 8 DNA in a patient with AIDS after protease inhibitor therapy

1997; Elsevier BV; Volume: 37; Issue: 4 Linguagem: Inglês

10.1016/s0190-9622(97)70188-9

1097-6787

Anne E. Burdick, Cynthia Carmichael, Peter L. Rady, Stephen K. Tyring, Evangelos V. Badiavas,

Cytomegalovirus and herpesvirus research

Kaposi’s sarcoma (KS) has been associated with the human herpesvirus 8 (HHV-8), also known as KS-associated HHV-8. 1Renne R Zhong W Herndier B et al.Lytic growth of Kaposi’s sarcoma associated herpesvirus (human herpesvirus 8) in culture.Nat Med. 1996; 2: 342-346Crossref PubMed Scopus (910) Google Scholar, 2Rady PL Yen A Martin III, RW et al.Herpesvirus-like DNA sequences in classic Kaposi’s sarcomas.J Med Virol. 1996; 47: 179-183Google Scholar, 3Chang Y Cesarman E Pessin MS et al.Identification of herpesvirus-like sequences in AIDS-associated Kaposi’s sarcoma.Science. 1994; 266: 1868-1869Crossref Scopus (4900) Google Scholar, 4Lebbé C Agbalika F de Crémoux P et al.Detection of human herpesvirus 8 and human T-cell lymphotropic virus type 1 sequences in Kaposi sarcoma.Arch Dermatol. 1997; 133: 25-30Crossref PubMed Google Scholar, 5Huang YQ Kaplan MH Poiesz B et al.Human herpesvirus-like nucleic acid in various forms of Kaposi’s sarcoma.Lancet. 1996; 345: 759-761Crossref Scopus (432) Google Scholar, 6Russo JJ Roy A Bohenzky RA et al.Nucleotide sequence of the Kaposi’s sarcoma–associated herpesvirus (HHV-8).Proc Natl Acad Sci U S A. 1996; 93: 14862-14867Crossref PubMed Scopus (1290) Google Scholar, 7Foreman KE Friborg J Kong W et al.Propagation of a herpesvirus from AIDS-associated Kaposi’s sarcoma.N Engl J Med. 1997; 336: 163-171Crossref PubMed Scopus (170) Google Scholar We observed a patient who had resolution of cutaneous and oral lesions after treatment with a protease inhibitor. Histopathologic and polymerase chain reaction (PCR) analyses for HHV-8 were performed on one KS lesion before protease inhibitor therapy and again at the same site once the lesion had regressed. A 30-year-old white man seropositive for HIV had multiple violaceous macules and plaques on his trunk, thighs, penis, and lower lip and a 3.0 × 5.0 cm violaceous nodule on his soft palate. His CD4 cell count was 46/mm3 and his HIV RNA by PCR (viral load) was 44,730 RNA copies/ml. A biopsy specimen from the right thigh revealed KS. His medications were zidovudine, lamivudine, inhaled pentamidine, clarithromycin, and acyclovir. Four months later, the patient started receiving the protease inhibitor ritonavir in addition to didanosine, trimethoprim-sulfamethoxazole, acyclovir, clarithromycin, folinic acid, fluconazole, and vitamins. After 1 month his KS lesions were notably smaller, his CD4 cell count had increased to 177/mm 3 , and his viral load had fallen to 1900 RNA copies/ml. After 4 months of ritonavir therapy, the cutaneous and oral KS lesions flattened, leaving macular pink hyperpigmentation. After 6 months the patient’s soft palate appeared normal, without hyperpigmentation, and his trunk and thigh lesions were clear centrally with surrounding mild hyperpigmentation. A biopsy specimen from the clinically regressed lesion on the right thigh revealed mild dermal cicatrix with scattered hemosiderin deposition. The amount of cicatrix present was considerably less than that typically seen in KS lesions treated with intralesional chemotherapeutic agents. A CD31 stain demonstrated that the number of vascular channels was reduced to a level within normal limits. DNA was extracted as described previously from two paraffin-embedded biopsy specimens from a cutaneous KS lesion of the patient before treatment, from the regressed lesion after ritonavir treatment, from fresh, normal control skin (negative control), and from an HHV-8–containing cell line 1Renne R Zhong W Herndier B et al.Lytic growth of Kaposi’s sarcoma associated herpesvirus (human herpesvirus 8) in culture.Nat Med. 1996; 2: 342-346Crossref PubMed Scopus (910) Google Scholar (BCBL1, positive control). 2Rady PL Yen A Martin III, RW et al.Herpesvirus-like DNA sequences in classic Kaposi’s sarcomas.J Med Virol. 1996; 47: 179-183Google Scholar The DNA was analyzed by PCR for the presence of KS330 233 viral region as previously described 3Chang Y Cesarman E Pessin MS et al.Identification of herpesvirus-like sequences in AIDS-associated Kaposi’s sarcoma.Science. 1994; 266: 1868-1869Crossref Scopus (4900) Google Scholar with the following modifications. The PCR reactions were performed in a blinded fashion. Amplification was carried out in 45 consecutive cycles. Amplification of the interferon gamma internal control gene was included to indicate the quality of DNA samples. Primers for the interferon gamma internal control gene were designed to give a 173 bp amplicon (position at nucleotides 251 to 422). 8Gray PW Goeddel DW Structure of the human immune interferon gene.Nature. 1982; 298: 859-863Crossref PubMed Scopus (375) Google Scholar Fragment fractionation of the PCR mixtures and the subsequent Southern blot procedure with oligonucleotide probes specific to the amplified DNA sequences of HHV-8 3Chang Y Cesarman E Pessin MS et al.Identification of herpesvirus-like sequences in AIDS-associated Kaposi’s sarcoma.Science. 1994; 266: 1868-1869Crossref Scopus (4900) Google Scholar and interferon gamma internal control gene were performed as described previously. 2Rady PL Yen A Martin III, RW et al.Herpesvirus-like DNA sequences in classic Kaposi’s sarcomas.J Med Virol. 1996; 47: 179-183Google Scholar Agarose gel electrophoresis and subsequent Southern blot analysis revealed characteristic PCR products specific for HHV-8 from the KS sample before protease inhibitor treatment and from the HHV-8–containing positive control BCBL1 cell line (Fig. 1 , A ). HHV-8 DNA was absent, however, in the clinically regressed lesion. To assess integrity and relative quantity of genomic DNA from the samples, a region of the interferon gamma internal control gene was amplified. The 173 bp interferon gamma internal control gene-fragment could be detected in all tissue samples (Fig. 1 , B ). HHV-8 DNA was also absent in DNA from normal skin and in the reagent control, excluding contamination during the amplification. Our results confirm the presence of HHV-8 in KS. 2Rady PL Yen A Martin III, RW et al.Herpesvirus-like DNA sequences in classic Kaposi’s sarcomas.J Med Virol. 1996; 47: 179-183Google Scholar, 3Chang Y Cesarman E Pessin MS et al.Identification of herpesvirus-like sequences in AIDS-associated Kaposi’s sarcoma.Science. 1994; 266: 1868-1869Crossref Scopus (4900) Google Scholar, 4Lebbé C Agbalika F de Crémoux P et al.Detection of human herpesvirus 8 and human T-cell lymphotropic virus type 1 sequences in Kaposi sarcoma.Arch Dermatol. 1997; 133: 25-30Crossref PubMed Google Scholar, 5Huang YQ Kaplan MH Poiesz B et al.Human herpesvirus-like nucleic acid in various forms of Kaposi’s sarcoma.Lancet. 1996; 345: 759-761Crossref Scopus (432) Google Scholar, 6Russo JJ Roy A Bohenzky RA et al.Nucleotide sequence of the Kaposi’s sarcoma–associated herpesvirus (HHV-8).Proc Natl Acad Sci U S A. 1996; 93: 14862-14867Crossref PubMed Scopus (1290) Google Scholar To our knowledge this is the first description of a decrease in the HHV-8 copy number to levels undetectable by PCR analysis in a regressed KS lesion from a patient with AIDS after protease inhibitor therapy. This PCR analysis can detect viral products obtained from approximately four target DNA molecules. 9Bigoni B Dolcetti R DeLellis L et al.Human herpesvirus 8 is present in the human lymphoid system of healthy persons and can reactivate in the course of AIDS.J Infect Dis. 1996; 173: 542-549Crossref PubMed Scopus (140) Google Scholar Literature data suggest that HHV-8 has oncogenic features, 6Russo JJ Roy A Bohenzky RA et al.Nucleotide sequence of the Kaposi’s sarcoma–associated herpesvirus (HHV-8).Proc Natl Acad Sci U S A. 1996; 93: 14862-14867Crossref PubMed Scopus (1290) Google Scholar so the activated virus in our patient may have contributed to the development of KS. Our observation that HHV-8 was undetectable in the regressed lesion suggests that the host immune defense is improved by this therapy. It is possible that didanosine, which was initiated at the same time as ritonavir, may have played a synergistic role in improving the patient’s immune status. Regression of the KS lesion in our patient after therapy was consistent with observations that reduction of immunosuppressive therapy in transplant recipients and in other clinical settings may result in regression of KS lesions. 10Penn I Incidence and treatment of neoplasia after transplantation.J Heart Lung Transplant. 1993; 12: S328-S336PubMed Google Scholar, 11Trattner A Hodak E David M et al.The appearance of Kaposi sarcoma during corticosteroid therapy.Cancer. 1993; 72: 1779-1783Crossref PubMed Scopus (146) Google Scholar Further studies are needed to determine the mechanisms by which protease inhibitor therapy in patients with AIDS results in regression of AIDS-associated KS marked by an immense reduction in viral copy number of HHV-8 to an undetectable level.