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AIDS Malignancies in the Era of Highly Active Antiretroviral Therapy

AIDS Malignancies in the Era of Highly Active Antiretroviral Therapy

ABSTRACT: The introduction of highly active antiretroviral therapy (HAART) has had a dramatic impact on the morbidity and mortality of individuals living with human immunodeficiency virus (HIV). In addition to contributing to dramatic declines in the incidence of several opportunistic infections, HAART is affecting the incidences of several acquired immunodeficiency syndrome (AIDS)-defining malignancies. The incidence of Kaposi’s sarcoma (KS) and primary central nervous system lymphoma (PCNSL) has dropped precipitously since the introduction of HAART in 1995. Systemic non-Hodgkin’s lymphoma (NHL) appears to be declining in incidence as well, but to a lesser degree than KS and PCNSL. On the contrary, the incidence of invasive cervical carcinoma has not significantly changed in the HAART era. The impact of HAART on the epidemiology of other HIV-associated malignancies, including Hodgkin’s disease and anal carcinoma, remains unclear. Data regarding the impact of HAART on the natural history and treatment outcomes of HIV-associated malignancies are limited. The possibility of direct and indirect roles of HIV in HIV-related carcinogenesis suggests that antiretroviral therapy may be an important component of the treatment strategy for several HIV-related malignancies. Patients with HIV-NHL treated with HAART in addition to chemotherapy experience fewer intercurrent opportunistic infections. Furthermore, the simultaneous administration of HAART and chemotherapy does not appear to significantly increase toxicity. Whether the combination of HAART and standard therapy results in improved survival remains uncertain. This two-part article, which began in the April 2002 issue, analyzes the impact of HAART on the incidence, clinical course, and outcomes of each of the AIDS-related malignancies. [ONCOLOGY 16:657-670]

Part 1 of this article, published in last month’s
issue, began an exploration of the introduction of highly active retroviral
therapy (HAART) and its dramatic impact on the morbidity and mortality of people
infected with the human immunodeficiency virus. The discussion focused mainly on
the acquired immunodeficiency syndrome (AIDS)-related malignancies Kaposi’s
sarcoma (KS) and non-Hodgkin’s lymphoma (NHL). Part 2 will conclude with an
examination of the impact of HAART on primary central nervous system lymphoma (PCNSL),
primary effusion lymphoma (PEL), cervical cancer and dysplasia, and the non-AIDS-defining
malignancies Hodgkin’s lymphoma and anogenital neoplasia.

Primary CNS Lymphoma

Approximately 1% of individuals with AIDS develop primary central nervous
system lymphoma.[1,2] PCNSL usually occurs in advanced stages of immune
dysfunction, typically with CD4 counts below 50 cells/µL.[2,3] Presumably,
the impact of immune reconstitution observed with HAART would be most apparent
in malignancies typically associated with severe immunosuppression. The effect
of HAART on the incidence and clinical course of CNS lymphoma is not yet clear.

Background

PCNSL in human immunodeficiency virus (HIV)-infected patients is uniformly
associated with Epstein-Barr virus.[4-6] The pathogenesis is unclear, but may
involve cellular transformation by Epstein-Barr virus gene products, including
Epstein-Barr virus latent membrane protein (LMP-1).[4] Transformation results in
overexpression of bcl-2, a protein that has been demonstrated to inhibit
apoptosis.

Patients with PCNSL usually present with confusion, memory loss, and
lethargy.[2,3,7] Focal neurologic defects—including hemiparesis, aphasia,
seizures, cranial nerve palsies, and headache—are not uncommon.[5] The
majority of patients have multifocal lesions on radiographic imaging.[1,8] Most
PCNSLs display a B-cell phenotype and diffuse large cell or immunoblastic
histology.[3,4]

The prognosis for individuals with HIV-PCNSL is very poor. If untreated,
median survival ranges from 4 to 8 weeks.[3,9] Radiation therapy may prolong
survival, but is used primarily as palliative treatment. Historically, the
majority of patients who complete adequate radiotherapy (3,000 to 5,400 cGy) die
from intercurrent opportunistic infections.[9,10]

In PCNSL occurring in seronegative individuals, the use of chemotherapy alone
or with radiation has transformed a once fatal disease into a potentially
curable disease. Prior to the use of high-dose methotrexate, the median survival
for HIV-negative individuals with PCNSL was 14 months, with only 3% to 26% of
individuals surviving 5 years.[11] Early data suggest that the use of high-dose
methotrexate, alone or in combination with radiotherapy, in non-HIV-related
PCNSL results in complete response rates of 65% and 2-year survival rates of
63%.[11]

Until recently, cytotoxic therapies effective in treating PCNSL, such as
high-dose methotrexate, have not been feasible in the profoundly
immunocompromised patients that typify this population. Jacomet and colleagues
treated 15 individuals with HIV-PCNSL with high-dose methotrexate (3 g/m² every
14 days × 6 cycles).[12] This patient population had a mean CD4 count of 30
cells/mL and a median Karnofsky performance status of 50. The complete response
rate was 50% with a median survival of 10 months. It is likely that the ability
to deliver adequate cytotoxic therapy to patients with HIV-PCNSL may
dramatically improve outcomes in the HAART era.

Impact of HAART

Demonstration of a decrease in the incidence of PCNSL in HIV-infected
individuals since the introduction of HAART is difficult given the small number
of cases. While several smaller studies have failed to demonstrate a significant
decrease in the incidence of PCNSL, two of the largest published studies
indicate a significant decline (Table 1).

The impact of HAART on treatment outcomes of HIV-PCNSL is likely to be
significant. At present, limited data exist, but anecdotal reports are
promising. At the very least, the improved immune function and decreased
incidence of opportunistic infections afforded by HAART may improve outcomes of
patients treated with radiotherapy. In addition, aggressive treatment of HIV-PCNSL
with systemic chemotherapy may become a realistic goal.

Interestingly, direct effects of HAART on PCNSL have been reported. Corales
and colleagues described two patients treated with HAART alone for HIV-PCNSL.[13]
Both patients had dramatic clinical responses and were alive at 8 and
21 months from the time of diagnosis. HAART regimens varied and were not
selected based on CNS penetration.

Freiberg and colleagues recently presented data demonstrating a possible role
for hydroxyurea in the treatment of HIV-PCNSL.[14] Hydroxyurea has previously
been shown to induce loss of Epstein-Barr virus episomes from lymphoblastoid-
and Burkitt’s lymphoma-derived cell lines. The investigators described two
patients with PCNSL who were treated with low-dose hydroxyurea (400 to 700
mg/m²/d) and HAART. Despite minimal improvement in CD4 count and viral load,
both patients showed dramatic improvement clinically and radiographically, with
survivals of 23 to 25 months. The authors concluded that the observed responses
were primarily due to Epstein-Barr virus-targeted therapy with hydroxyurea,
given the lack of demonstrated immune reconstitution with HAART.

Future Directions

Further investigations exploring the use of antiviral therapy are under way.
Previously, Raez and colleagues demonstrated a 43% complete response rate in
seven patients with HIV-PCNSL treated with intravenous zidovudine (Retrovir),
ganciclovir (Cytovene), and interleukin (IL)-2.[3,15] In vitro data have shown
that some B cell lymphoma cell lines undergo apoptosis after exposure to
zidovudine and ganciclovir.[16] As a result of these observations, the AIDS
Malignancy Consortium is planning a phase II study investigating the use of
induction intravenous zidovudine, ganciclovir, and IL-2 followed by maintenance
subcutaneous IL-2 and oral ganciclovir in patients with HIV-PCNSL. All patients
will be treated with HAART for the duration of the study.

Primary Effusion Lymphoma

Primary effusion lymphoma (PEL), also called body cavity-based lymphoma, is
an aggressive non-Hodgkin’s lymphoma found primarily in HIV-infected
individuals. PEL accounts for 1% to 5% of all AIDS-related NHL.[3] Clinically,
PEL presents as malignant effusions in patients with advanced AIDS.[17,18] The
usual nodal and extranodal solid tumors associated with sytemic HIV-NHL are
notably absent in patients with PEL.[17] High-grade immunoblastic morphology is
characteristic.[17] Immunohistochemistry reveals a null phenotype, devoid of
typical B- and T-cell markers.[17,18] The presence of human herpesvirus-8
(HHV-8) can be demonstrated in all HIV-related PELs, and clonal Epstein-Barr
virus is frequently, though not universally, found.[4,18,19] Men who report a
history of sex with men are disproportionately affected by PEL.[18] Up to 50% of
patients have a prior history of Kaposi’s sarcoma.[18,20]

The pathogenesis of PEL is not clear, but the strong association with HHV-8
is suggestive of a viral role in lymphomagenesis. HIV-related PELs express
several HHV-8 encoded gene products that affect B-cell growth, including vIL-6
and viral cyclin.[4,18] Antibodies targeting the IL-6 signaling pathway have
inhibited clonal growth of AIDS-PEL in vitro and in an animal model.[21] Given
the significant percentage of PELs that demonstrate coinfection with
Epstein-Barr virus and HHV-8, a possible second-hit model of lymphomagenesis is
possible.[4]

The prognosis for HIV-infected individuals with PEL is grim, with
a median survival of only 3 to 5 months.[18] Many patients are critically
ill at the time of diagnosis, making systemic chemotherapy difficult to
administer. Historically, most patients who are treated receive combination
chemotherapy regimens used in other aggressive HIV-related lymphomas.[18] No
standard therapy currently exists for this rare lymphoma.

Impact of HAART

Given the rarity of PEL, it is not surprising that few data exist regarding
the impact of HAART. Emerging data suggest that antiviral therapy may be
effective in PEL.

Recently, Boulanger and colleagues presented retrospective data involving a
series of 12 patients with HIV-related PEL. Eight of the patients died from 3
weeks to 8 months after diagnosis.[20] Three had prolonged survivals with a
variety of treatment strategies, including interferon-alfa plus cidofovir
(Vistide) in one, high-dose chemotherapy in one, and initiation of HAART in the
third.

Additionally, Berryman presented a case report of a patient with advanced
AIDS and aggressive PEL who was treated with lamivudine (Epivir), stavudine
(Zerit), abacavir, and nelfinavir (Viracept).[22] The patient achieved a
complete remission within 6 weeks and was alive without evidence of lymphoma
after 8 months of follow-up.

As the roles of HHV-8 and Epstein-Barr virus in the development of PEL are
elucidated, pathogenic-based therapy will continue to be developed. Currently,
the initiation of HAART appears to be an important component of the therapeutic
strategy.

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