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AIDS-Related Cancers in the Era of Highly Active Antiretroviral Therapy

AIDS-Related Cancers in the Era of Highly Active Antiretroviral Therapy

ABSTRACT: Highly active antiretroviral therapy (HAART) has shown great efficacy in reducing human immunodeficiency virus levels, increasing immunity, and prolonging the survival of persons with acquired immunodeficiency syndrome (AIDS). The risk of life-threatening infections has been greatly reduced. However, the impact of HAART on the incidence of malignancy has been less clear. Published studies generally show that the risk of developing Kaposi’s sarcoma declined by about two-thirds between 1994 and 1995 and from 1996 onward (considered the HAART era). Even before 1994, the risk for Kaposi’s sarcoma in persons with AIDS had declined considerably and this cancer has now become relatively uncommon. The mechanism by which this decline in incidence was achieved appears to involve improved immunity. Data on the reduction in the risk for non-Hodgkin’s lymphoma are mixed. Several studies conducted between 1997 and 1999 found no reduction in the risk for non-Hodgkin’s lymphoma, although the most recent data (from 1997 to 1999) show a 42% decrease in risk. Even with a one-third reduction, the risk for non-Hodgkin’s lymphoma remains considerably elevated. This high risk may be related to the fact that HAART therapy does not restore the immune system to normalcy. The increased lymphocyte turnover, with its accompanying risk of genetic errors, may increase the risk of developing non-Hodgkin’s lymphoma. Most reports have insufficient data to analyze the impact of HAART therapy on incidence of central nervous system lymphomas, but recent data (from 1997 to 1999) showed a significant reduction in that risk. The mechanism by which this might occur is unclear because the central nervous system is an immunologic sanctuary. The relatively low incidence of other cancers in persons with AIDS makes it difficult to gauge the effect of HAART on their incidence, but to date, no significant trends have been reported for specific tumor types or for the overall risk of non-AIDS-related cancers. [ONCOLOGY 15(4):439-449, 2001]

Introduction

Kaposi’s sarcoma and non-Hodgkin’s lymphoma are
considered acquired immunodeficiency syndrome (AIDS)-defining illnesses. Although
invasive cervical carcinoma is less clearly related to the human
immunodeficiency virus (HIV) and/or AIDS, it is also accepted as
AIDS-defining.[1] In addition, persons with HIV/AIDS have been found to be at
increased risk for several other cancers—most prominently, Hodgkin’s disease
and anal cancers.[2] Other sites, especially conjunctival tumors and testicular
cancer, have also been reported in some registry studies and case reports,
although the small increases in the relative risk observed make it difficult to
convincingly associate these cancers with AIDS.

The pathogenesis of AIDS-related cancers (ie, Kaposi’s sarcoma
and non-Hodgkin’s lymphoma) is generally considered to be directly related to
immunosuppression rather than HIV infection.[3] The logic behind this
supposition is compelling. The malignant cells themselves are not infected with
HIV. Moreover, persons with HIV are not at exceptional risk for these cancers
(at least at a detectable level) unless they are also immunosuppressed. In
addition, persons who are immunosuppressed for reasons other than HIV infection
(eg, iatrogenic or genetic causes) are at risk for these same types of cancer.
Some investigators suggest that Tat, a protein expressed by HIV, may be linked
to the increased incidence of Kaposi’s sarcoma,[4] but even if this proves
correct, this incidence is greatly increased only among those in whom there is
concomitant immunosuppression.

If immunosuppression underlies the occurrence of these
malignancies, then ameliorating the immunodeficiency should markedly reduce the
risk of developing cancer. The advent of highly active antiretroviral therapy
(HAART) for persons with AIDS presents the opportunity for examining this
hypothesis. Strong evidence exists that HAART results in impressive reductions
in HIV replication and is usually associated with improvements in the CD4
lymphocyte counts of persons with immunosuppression.[5] As expected, these
improvements in immunity have greatly reduced the incidence of AIDS-associated
opportunistic infectious diseases.[6] In this review, we will examine the
evidence that they have also decreased the incidence of cancer in persons with
AIDS.

Antiretroviral Therapies

The extent to which antiretroviral therapies might influence
HIV-related immunosuppression depends on their efficacy in improving immunity
and how widely such therapies are used in persons with HIV/AIDS. In 1987,
monotherapy with zidovudine (azidothymidine or AZT [Retrovir]) was shown to be
effective in improving prognosis.[7] The clinical response was justifiably
attributed to improvements in immunity as measured by increasing CD4 cell
counts, although it is also possible that lowering HIV levels further improved
immunity by affecting functional immunity in still-viable lymphocytes.[8]

In practice, clinicians soon observed that the improvement in
immunity following zidovudine therapy was transitory. Within 6 to 12 months,
therapy-resistant HIV variants emerged, high viral levels returned, and the
deterioration of immunity resumed. Later studies confirmed that the long-term
benefit was minimal,[9] and the need for combination antiretroviral regimens
became obvious.

During the 1990s, many new antiretroviral agents were licensed,
and others continue to be developed. The introduction of effective protease
inhibitors in the mid-1990s has been especially important. Clinical trials have
demonstrated that these drugs, used in combination, are highly effective in
blocking HIV replication for prolonged periods.[10] In many persons, viral
levels fall below the level at which they can be detected even with sensitive
tests.

Highly Active
Antiretroviral Therapy

Dual drug therapies also came into wide use in the early 1990s,
and since 1996, triple-drug regimens that include protease inhibitors have been recommended for persons with clinically
significant HIV-related immunosuppression. Figure 1, based on data reported by
the Centers for Disease Control and Prevention (CDC),[11] illustrates the
proportion of persons with HIV/AIDS who were taking these drugs in the United
States between 1992 and 1997.

Highly active antiretroviral therapy with protease inhibitor
drugs blocks HIV replication, resulting in meaningful improvements in the
clinical status and prognosis of many persons infected with HIV. This strategy
demonstrates that good HIV control and an increase in the CD4 count are
associated with enhanced improvement in defending the host against environmental
pathogens. Moreover, these results have revolutionized the care and prognosis of
HIV patients, leading to the reasonable expectation that persons with HIV
infection can survive for many years, even after an AIDS diagnosis.

Despite these encouraging developments, there are several
serious caveats concerning the impact of HAART therapy on cancer risk trends.
Foremost is the fact that many HIV-infected persons are not receiving HAART.[11]
Some people are not aware that they are HIV-infected until they develop an
AIDS-defining illness (which may be cancer). For others, such as those with
dementia or drug addiction problems, the complex regimens are beyond their
ability to support or maintain. Still others cannot tolerate the side effects of
the drug combinations. Finally, even among those who take full HAART regimens,
breakthrough HIV infections from resistant strains can occur.

It is reasonable to hope that newly developed antiretroviral
drugs will
lead to easier administration, lower toxicities, and control of HIV viremia. In
the interim, however, there continues to be a population of HIV-infected,
immunosuppressed persons who
are not receiving effective anti-HIV therapy.

Immune Response Does
Not Normalize

Even among those who respond well to HAART, the immune responses
of severely immunocompromised subjects typically do not return to normal.
Rather, in seriously immunocompromised subjects, CD4 counts increase from
dangerously low levels of less than 50 cells/mL to perhaps 200 to 300
cells/mL.[12] At this level, immunity is not normal (normal CD4 levels are above
500 cells/mL), but the risk of developing a major life-threatening disease is
much less.

One unexpected consequence of HAART’s success is the
increasingly recognized phenomenon of immune reconstitution disease, in which
symptoms appear in direct relation to the improvement in immunity.[13,14] In
these syndromes, the host recognizes and reacts to low-grade infections that
were not apparent earlier, such as may occur with Mycobacterium
avium-intracellulare
and hepatitis C virus. This reaction can be so severe as to
be fatal. Thus, the immunity that is measured as marginally deficient by
conventional CD4 counts can have highly reactive clones that are proliferating
robustly because of stimulation from smoldering infections. These activated
clones may affect the risk of developing cancer, especially the lymphomas, in
ways that obscure a relationship to HAART.

Kaposi’s Sarcoma

The proportion of AIDS patients presenting with Kaposi’s
sarcoma has declined over time. There are several explanations for this change.
Public health data often record only the first AIDS-defining illness. Early in
the AIDS epidemic, most AIDS cases were identified on the basis of a diagnosis
of Kaposi’s sarcoma or Pneumocystis carinii pneumonia. However, as the
understanding of the range of AIDS-associated diseases increased, the definition
of AIDS expanded to include other conditions.

In the most recent definition of an AIDS case, formulated in
1993, the CDC changed the definition to include HIV-infected persons who have no
overt illness but are immunosuppressed (CD4 < 200 cells/mL or < 14%) to
the point of being at risk for an AIDS-defining illnesses.[1] This expansion of
the diagnosis has allowed recognition of other conditions as being AIDS-related
before the appearance of Kaposi’s sarcoma.

Even in data sets that include both onset and a later diagnosis
of Kaposi’s sarcoma, however, the incidence of the disease has declined. Some
of this decline can be attributed to changes in the population of HIV-infected
persons in the United States. Among persons with AIDS, the incidence of Kaposi’s
sarcoma varies considerably by group. Initially, the majority of AIDS cases
occurred in homosexual men, a group with an 8- to 10-fold higher risk for Kaposi’s
sarcoma than other groups.[3] Moreover, most cases were in white men, a group
that has at least twice the risk for Kaposi’s sarcoma compared to black men,
even after controlling for HIV-exposure groups. However, the population of AIDS
patients who are white homosexual men has declined as a proportion of all AIDS
cases, whereas the percentage who are black men, both homosexual and otherwise,
has increased, thus progressively enriching the mix of newly diagnosed AIDS
cases with persons at lower risk for Kaposi’s sarcoma. The impact of HAART on
risk for Kaposi’s sarcoma needs to be assessed carefully against this
backdrop.

Kaposi’s Sarcoma and HAART

Almost all reports have noted declines in the incidence of
Kaposi’s sarcoma between the early 1990s and the post-1996 era (Table
1
).[15-21] In summary, between 1994 and 1995 and from 1996 onward (the HAART
era), the incidence of Kaposi’s sarcoma declined by about two-thirds, to the
point that it is now an uncommon diagnosis in people with AIDS.

However, a temporal approach does not prove a relationship to
HAART because the decline in Kaposi’s sarcoma incidence long preceded the
introduction of this therapy. In part, the change in the definition of AIDS and
shifts in the population that became infected with HIV contributed to that
decline, as discussed above. Additionally, the early, less effective,
antiretroviral regimens may have reduced the incidence of Kaposi’s sarcoma,
although statistical evidence supporting this association is inconclusive.[15]

More speculatively, we now understand that Kaposi’s sarcoma
requires infection with a newly described herpesvirus, HHV-8,[22] which is
common among homosexual men.[23] This virus appears to have been co-epidemic
with sexually transmitted HIV.[24,25] Possibly, burnout of the HHV-8 epidemic,
along with exhaustion of the population susceptible to Kaposi’s sarcoma, could
have contributed. Persons who acquire HHV-8 while HIV-infected (and presumably
immunosuppressed) have a 2.5-fold increased risk of developing Kaposi’s
sarcoma over that of persons who were already infected with HHV-8 when they
became infected with HIV.[26]

Impact on Immunity

Nevertheless, there is compelling extrinsic and intrinsic
evidence that improved immunity is probably the major factor influencing the
reduction in the incidence of Kaposi’s sarcoma. Extrinsically, case reports
describe improvement or even resolution of preexisting Kaposi’s sarcoma in
persons who began receiving HAART.[27-31] Some reports suggest that this
clinical effect is particularly potent in combination antiretroviral drug
regimens containing protease inhibitors.[30,31]

Given its impact on existing Kaposi’s sarcoma tumors,
treatment with HAART would be expected to prevent incipient tumors.
Intrinsically, in several published reports, the "breakthrough" cases
of Kaposi’s sarcoma that occurred in the HAART era were observed only among
men who did not receive potent antiretroviral therapy.[15,20]

Also supporting a direct role for HAART (through its impact on
immunity) is a report that examined the risk of illnesses in HIV-infected
persons started on HAART. Investigators from the Swiss HIV Cohort Study examined
the risk for Kaposi’s sarcoma and other diseases.[32] Case numbers are
somewhat marginal for strong conclusions, but their results showed a significant
difference in the incidence of Kaposi’s sarcoma between the 6 months just
before HAART and the 6 months immediately after HAART.

This decline in incidence implied that HAART had an almost
immediate impact. Overall, the risk declined by 66% during the 15 months after
HAART was initiated (P = .001, compared to the pre-HAART period). While such
data are subject to analysis problems that complicate their interpretation,[33]
they nevertheless demonstrate a decreased risk for Kaposi’s sarcoma
specifically related to HAART in a study in which each subject served as his or
her own control.

Supplemental Study

As a supplemental study for this report, I examined cancer risk
in 309,365 persons with AIDS in the AIDS-Cancer Match Registry Study.[34] More
than 21,000 cases of Kaposi’s sarcoma were reported in AIDS patients, the
majority of which were AIDS-defining illnesses. Cancer incidence in persons with
AIDS cannot be easily quantified when the cancer defines AIDS onset, because the
number of subjects at risk is unknown. However, persons with AIDS-defining
conditions other than Kaposi’s sarcoma can be used to define a true cohort, in
which incidence can be determined. To limit loss to follow-up bias, the analysis
was confined to the 2-year period (4 to 27 months) after the onset of AIDS.

In data presented in Figure 2, the analysis was further
restricted to white men so as to minimize the impact of race and sex, and age
was adjusted to accommodate temporal changes in the age distribution of the men
developing AIDS. The time span permitted a comparison of incidence
determinations for the pretherapy periods (1980-1983 and 1983-1986), the era
of monotherapies (1987-1989), and the time when dual therapies were available
(1990-1993 and 1994-1996). Cancer data were available for only a few of the
registries through 1996, and cancer risk in the true triple-therapy HAART era is
therefore incomplete. Except for the earliest period, the number of Kaposi’s
sarcoma cases in each period was impressive (total: 5,312 in homosexual men and
563 in heterosexual men).

After the introduction of zidovudine in 1987, the incidence of
Kaposi’s sarcoma declined steadily until the last data group in 1994-1996 (Figure
2
). This decline might have been affected by changes in therapy, because
antiretroviral strategies continued to improve in each period after 1986 and
also became more widely distributed.

It should be noted that when the last available data for this
analysis were generated (1994-1996), relatively few men would have received
protease-containing antiretroviral therapy. However, the proportion of men who
received optimal HIV-suppressive therapies would likely have been higher among
white homosexuals (the group at highest risk for Kaposi’s sarcoma) than in the
general population of white heterosexuals.

Thus, the evidence strongly suggests that HAART has further
reduced the incidence of Kaposi’s sarcoma. That incidence declined by about
two-thirds from 1994-1995 to 1996 and later, when HAART became widely
available. This decline occurred when the incidence of Kaposi’s sarcoma in
persons with AIDS had already decreased from earlier years. Kaposi’s sarcoma
is now uncommon among persons with AIDS who are receiving effective
antiretroviral therapy.

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