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The Ultimate Gift
A
newsletter from the transplant team
at Rhode Island Hospital
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Management of the HIV Positive
Transplant Patient
by Reginald Gohh, MD
Renal transplantation is the treatment of choice for most caused
of ESRD, providing not only improved quality of life, but also superior
long-term outcomes. However, patients with certain illnesses have
traditionally been excluded from transplantation because of the
known morbidity associated with immunosupression. Generally, these
have been individuals with diseases in which an intact immune system
has been felt to be more important to the survival of the patient
than renal function. These include certain cancers, chronic infectious
states, and immune deficiency states. In the past, HIV infection
has been viewed in this category, both for it historically poor
prognosis independent of renal failure and because of the concern
that anti-rejection therapy in an immunocompromised individual would
exacerbate the underlying disease.
However, in the past six years, tremendous advances have been made
in the management of the HIV infected patient. The development of
HIV-1 specific protease inhibitors (PIs) and more potent HIV reverse
transcriptase inhibitors have led to the concept of multi-drug combination
regimens that effectively suppress HIV replication. The widespread
adaptation of these highly active anti-retroviral therapies (HAART)
is the principal reason for the dramatic decline in HIV-related
mortality that has occurred since 1995(Figure 1, Palella, et al.,
NEJM, 1998) As life expectancy increases in this patient population,
it stands to reason that there will be an increased incidence of
end stage renal disease patients resulting from both HIV and non-HIV
causes.
Figure 1: Trends in Age-Adjusted* Rates of Death due to HIV Infection,
USA, 1982-1998
Several different renal syndromes have been described inpatients
infected with HIV. HIV-associated nephropathy (HIVAN) is the leading
cause of ESRD in HIV-infected patients (Klotman, Kidney Int 2005;
56). It occurs almost exclusively in HIV-infected African Americans
and occasionally in Hispanics, by rarely in Caucasians. Patients
with HIVAN present clinically with nephrotic range proteinuria and
progressive renal insufficiency with histologic findings of focal
segmental glomerulosclerosis and microcystic tubulo-interstitial
disease. Currently, HIVAN has emerged as the third leading cause
of ESRD in the African-American population (ages 20-64) and accounts
for 10% of new cases of ESRD in this group. Thrombotic microangiopathies
and immune-complex mediated renal diseases (including IgA nephropathy)
are also linked with HIV infection and can lead to ESRD (Kimmel,
Curr Opin Nephrol Hypertens 2005; 9). Additionally, since HIV-infected
patients are living longer, ESRD from non-HIV causes such as diabetic
nephropathy and hypertension disease can be expected to develop
in a significant fraction of this patient population. As a result,
the number of HIV (+) patients undergoing dialysis can be expected
to increase. According to the USRDS, AIDS and HIV are listed as
comorbidities for 0.4% and 0.7% of the total dialysis population,
respectively.
There is paucity of information regarding the outcomes of
solid organ transplantation in HIV (+) patients. However, a number
of anecdotal retrospective cases from the pre-HAART era suggest
that although solid organ transplantation in this patient group
was sub-optimal, it certainly was not abysmal. In fact, there are
two reports of HIV (+) patients undergoing liver or renal transplantation
respectively who have demonstrated normal graft function for at
least 8 years (Jacobson, et al., Lancet 1991; 337, Ahuja et al.,
Am J Nephrol 19971 17). Since the HIV status of these two patients
was unknown prior to transplant, no attempts were made to alter
their immunosuppressive therapy. Furthermore, Tzakis and colleagues
at the University of Pittsburgh analyzed the AIDS-free time between
HIV (+) transplant recipients and HIV (+) control groups who contracted
their disease through blood transfusions (Tzakis, Transplantation
1990; 49). By Kaplan-Meier analysis, the proportion remaining in
AIDS-free was not statistically different between the different
groups for the five-year follow-up period. It should be noted that
these individuals were transplanted before the availability of HAART.
The dramatic improvement in anti-retroviral therapy and patient
survival since then suggests a need for individual transplant centers
to re-evaluate the policy of excluding HIV-infected patients from
renal transplantation. However, in a national random survey using
hypothetical patient scenarios, U.S. nephrologists would have been
recommended only 3.3% of all HIV(+) patients for transplantation
(Thamer, et al., Transplantation 2005,71).
Although seemingly counterintuitive, from a theoretical perspective,
current immunosuppressive therapies may actually improve the course
of HIV disease rather than exacerbating the underlying process.
Unfortunately, to date there are no definitive clinical data to
support this hypothesis. When used in conjunction with HAART, immunosuppressive
therapies such as cyclosporine and mycophenolate can improve outcomes
in HIV-infected patients by three mechanisms: (1) reducing the number
of activated lymphocytes required for HIV replication; (2) acting
directly as antiviral agents; and (3) improving the bioavailability
of concurrent anti-retrovirals. Both cyclosporine and mycophenolate
mofetil (MMF) can reduce the number of activated T-cells needed
for HIV replication, thus limiting the propagation of the infection
(Chapuis et al., Nat Ned 2005; 6, Karpas et al., Proc Nati Acad
Sci USA 1992; 89). Acting as a nuclear import of HIV-1 DNA in active
CD4+ T cells (Emmel et al., Science 1989; 246). Conversely, MMF
may potential the anti-retroviral effect of other HAART components
by selectively inhibiting the production of guanosine nucleotides
necessary for DNA replication (Margolis, et al., J Acquir Immune
Defic Syndr 2005; 21). Finally, cyclosporine may also improve the
absorption of protease inhibitors by inhibiting a cellular efflux
transporter molecule (P-gp) that actively pumps these medications
out of cells (Schwartz, et al., Transplantation 1993; 55).
However, from a clinical perspective, there are significant pharmacokinetic
difficulties when combining anti-rejection and anti-retroviral therapies.
A HAART regimen typically consists of a combination of HIV protease
inhibitors (PIs) or a non-nucleoside reverse transcriptase inhibitor
(NNRTI) plus necleoside reverse transcriptase inhibitors (NRTIs).
The PIs, NNRTIs, and immunosuppressants such as cyclosporine, tacrolimus
and sirolimus share the CYP3A4 metabolic pathway. Thus, there is
significant potential for drug-drug interactions when these drugs
are used concomitantly. All protease inhibitors, particularly ritonavir,
are potent inhibitors of CYP3A4. Conversely, the NNRTIs can be both
inhibitors and inducers of the enzymatic pathway.
Several case reports have documented marked increases in
cyclosporine and tacrolimus concentrations when protease inhibitors
(ritonavir, saquinavir, or nelfinavir) were added to these regimens.
In one such case, the combination of ritonavir and saquinavir added
to cyclosporine resulted in graft dysfunction in a kidney transplant
recipient (Smak et al., Transplantation 2005, 68). The cyclosporine
levels remained over 1,000 ng/ml for more than ten days despite
discontinuation of the drug. In our own lab, using a HIV- infected
patient with ESRD as a model, the combination of ritonavir and a
single dose of tacrolimus (O.I mg/kg) provided therapeutic drug
levels of the latter agent for over a week with an AUC estimated
in the order of 4-5 days (Figure 2, unpublished data). Although
anecdotal) these reports demonstrate severe interactions that cannot
simply be overcome by dose reduction. The development of analytical
methods for the accurate quantification of both immunosuppressive
drugs and anti-retroviral agents are a prerequisite for the evaluation
of the pharmacokinetic interactions between these drugs.
In summary, HIV disease has become a significant cause of
renal failure. Although renal transplantation is the treatment of
choice for most patients with ESRD, this option is currently not
widely available in this setting. However, the improvements in HIV
outcome certainly warrant a reevaluation of this option for select
patients. These individuals would obviously need to be clinically
stable, with CD4+ T cell counts >200/mm3 and detectable HIV viral
loads for an extended period. Furthermore, the issues regarding
the pharmacologic incompatibilities between anti-rejection and anti-retroviral
regimens need to be clarified before proceeding with clinical protocols.
Since immunosuppression is clearly associated with infectious and
malignant morbidity, and given the limited nature of the donor supply,
it might be rational to initially limit the transplantation of HIV-infected
individuals to those with available living donors. This would not
only minimize the risk of delayed graft function and thereby limit
the need for induction therapy, but also maximize the potential
for prolonged graft survival.
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