PI Perspective #24
April 1998 View PDF
Opportunistic Infections Update
The overall incidence of opportunistic infections (OIs) has significantly
decreased since the availability of highly active antiretroviral
therapy (HAART). While there is evidence that HAART results in significant
and clinically relevant immune recovery in many people, it is not
immediate and not complete.
Although the improved immune response associated with HAART has
been shown to delay progression and relapse of various HIV-related
infections,it may not control infections that have already started,
and are just beginning to establish themselves, at the time that
HAART is initiated. While the use of HAART has dramatically decreased
the overall incidence of OIs, HAART doesn’t work for everyone,
for a variety of reasons. Thus, it has not eliminated all OIs nor
has it eliminated the need for preventative or maintenance therapies
in all cases. More research is clearly needed to determine the appropriate
use of preventative and maintenance medications in this new era
of anti-HIV treatment.
Mycobacterium avium Complex (MAC)
A study recently provided insight into something being termed “MAC
reversal syndrome.” The study showed that individuals who
already have MAC when initiating HAART sometimes have an unusual
inflammatory response due to increased immune function. This syndrome
involves fevers and the growth of a mass or masses usually around
the neck or spine. The addition of prednisone appeared to lessen
the inflammatory reaction. Over time, these individuals still benefited
from HAART with dramatic decreases in HIV levels and increases in
CD4+ cell counts and their MAC infection stabilized. Thus, HAART
does not necessarily prevent MAC in persons fostering infection,
but ultimately seems to be beneficial whether or not MAC occurs.
While this study is small, it suggests that people who have active
manifestations of MAC, such as fevers and other symptoms, should
remain on HAART and anti-MAC therapies during such an episode.
Tuberculosis (TB)
A recent multinational study of 1,583 people who were both HIV-positive
and PPD-positive (positive for TB) found that two months of rifampin
(600mg once a day) + pyrazinamide (20mg/kg once a day) was just
as effective at preventing active TB as twelve months of isoniazid
(INH) (300mg once a day). INH has long been considered the gold
standard for preventing TB. There was no difference in the magnitude
of side effects between the two regimens. As expected, adherence
in the two-month regimen was significantly better, with 80% of people
completing the two-month regimen compared to less than half completing
the INH regimen. This shorter course of therapy is particularly
interesting because HIV infection is known to hasten the progression
of TB disease as well as increase the rate of activation of latent
TB infection. Furthermore, some studies have found that TB can further
stimulate HIV replication. Therefore, a shorter course of therapy
which might improve adherence would be particularly beneficial for
people who are co-infected with HIV and TB. Additionally, this short-course
regimen is likely to be less expensive than a year of INH–perhaps
allowing countries which currently cannot afford the use of INH
to start TB prevention campaigns. The rifampin + pyrazinamide combination
provides a safe and effective regimen for the prevention of TB,
however, there are significant potential drug interactions associated
with the use of rifampin which may impact a person’s decision
to opt for this regimen.
Pneumocystis carinii Pneumonia (PCP)
Several studies looking at PCP preventative regimens in the era
of HAART still show occasional breakthrough cases of PCP. All studies
confirm the use of TMP/SMX (Bactrim or Septra) as the first line
preventative therapy. For those who are intolerant to TMP/SMX, data
from two studies covering a total of 1,057 people compared dapsone
(100mg once a day) and atovaquone suspension (Mepron) (1,500mg once
a day) for the prevention of PCP. Results from the combined studies
showed the two therapies to be equally effective. Additionally,
there was no difference in the incidence of toxoplasmosis between
the two groups. This was somewhat of a surprise since dapsone has
been the drug of choice for those who can not tolerate TMP/SMX.
Additionally, there has been concerns that the original version
of atovaquone was not absorbed well into the bloodstream resulting
in insufficient blood levels of drug to prevent PCP. The new studies
used an improved formulation of atovaquone. People receiving dapsone
were more likely to develop rash and anemia (a decrease in red blood
cells) while people receiving atovaquone were more likely to experience
gastrointestinal side effects. In this large study, people receiving
atovaquone had fewer drug discontinuances than people receiving
dapsone, suggesting that atovaquone may be preferable to dapsone
for people who cannot tolerate the standard therapy (TMP/SMX).
A second study also confirms atovaquone as a useful second line
therapy for PCP prevention for people who can not tolerate standard
therapy (TMP/SMX). Four hundred and seventy-six people received
aerosolized pentamidine (Nebupent) (300mg monthly) or one of two
doses of atovaquone suspension (either 1,500mg or 750mg once a day).
There were no differences in the number of PCP cases between the
three groups. People receiving either dose of atovaquone were significantly
more likely to develop rash while people receiving aerosolized pentamidine
were more likely to develop bronchospasms.
Candidiasis
As with all other OIs, the rates of candidiasis or thrush have decreased.
Several studies have looked at the role of maintenance therapy (to
prevent the recurrence of thrush) for people who have a history
of recurrent thrush but are responding well to HAART. One study
found that withdrawal of azole-suppressive therapy, such as fluconazole
(Diflucan) and itraconazole (Sporanox), for maintenance of recurrent
thrush in people responding to HAART did not result in significant
relapse. Only two of twenty people had any recurrence of candidiasis
after withdrawal of maintenance therapy. In both cases, it was a
single episode controlled with a short course of fluconazole and
there was no further recurrence during the median 5 months of follow-up.
This would suggest that for those people experiencing immunologic
and virologic responses to HAART, need for maintenance therapy may
lessen over time, as the immune system recovers.
For people with candidiasis not responsive to standard therapy,
a small study found that three people resolved their disease with
the use of GM-CSF (Leukine, 300 micrograms/subcutaneous (under the
skin for 14 days) as an adjunctive therapy to fluconazole (400mg/once
a day). While the numbers here, again, are quite small, further
investigation into the use of GM-CSF in this setting is warranted.
Cryptosporidiosis / Diarrhea
Nitazoxanide (NTZ) is an anti-parasite compound recently submitted
to the Food and Drug Administration for consideration for approval
for its antidiarrheal activity. In studies, NTZ has been shown to
decrease stool frequency by at least 50% in about 40% of people
who have thus far received the drug. About 20% of people have had
a complete response with no cryptosporidium eggs (oocysts) detectable.
NTZ is dosed at 500mg twice a day and escalated to 1,000mg twice
a day if no response is seen in a minimum of four weeks. This is
the first evidence of a single drug having activity against cryptosporidiosis.
It is likely that NTZ in combination with other antiparasitic drugs
may have even better activity against cryptosporidiosis.
A recent study showed that paromomycin (Humatin) (1 gram twice
a day) and azithromycin (Zithromax) (600mg once a day), used in
combination, may also be an effective treatment for cryptosporidiosis.
This is important as neither drug alone has shown efficacy against
this organism. In this study, volunteers experienced marked reductions
in oocysts, 40% reduction in the number of stools per day and a
reduction in overall stool volume per day.
CMV
In the search for new classes of drugs, fomivirsen (formerly known
as ISIS 2922), an antisense drug against CMV, was studied in 28
people with newly diagnosed CMV retinitis. People received either
immediate or deferred therapy. Participants were given 150µg
by direct injection into the eye once weekly for three weeks, and
then put on maintenance therapy at 150µg once every other
week. The deferred therapy group had progression of their CMV retinitis
in a median time of 13 days compared to 71 days for the immediate
treatment group. The most common side effects were increased pressure
in the eye. This study shows that fomivirsen may be a useful drug
for the treatment of CMV retinitis. Additionally, laboratory studies
show that fomivirsen is active against CMV which is resistant to
other commonly used anti-CMV therapies such as ganciclovir (Cytovene),
foscarnet (Foscavir) and cidofovir (Vistide). However, these results
do not compare favorably with those seen from some other treatments
for CMV, most notably the ganciclovir implants, which offer a much
longer “time to relapse” than that cited here. Other
new drugs under study for CMV include valganciclovir, a new and
much more potent form of oral ganciclovir. All studies of new drugs
for CMV remain hampered by slow recruitment rates caused by the
success of HAART in preventing new incidences of CMV.
Kaposi’s Sarcoma
At last year’s conference there were several anecdotal reports
of resolution of Kaposi’s Sarcoma (KS) occurring concurrent
to viral load decreases observed as a result of highly active anti-HIV
regimens that included a protease inhibitor. This year a French
group reported on 13 people with KS, eight had cutaneous KS (skin
lesions) and five had pulmonary (in the lung) KS. Participants were
followed for one year after initiating a highly active protease
inhibitor containing regimen. Study participants were also allowed
to employ conventional chemotherapy for treating KS in concert with
a three-drug regimen. Among those with pulmonary KS, 3 of 5 experienced
a complete response (i.e. resolution of KS) and four of the five
are still alive 15 months after the initiation of the study. This
type of response, particularly among people with pulmonary KS, has
not been previously observed with chemotherapy alone. Among those
with cutaneous KS, 4 of 8 experienced a complete response. Remission
of KS, in this study, is also associated with a decrease in levels
of HHV-8 (also known as KSHV), a herpes family virus believed to
be associated with Kaposi’s Sarcoma.
Another study showed a correlation with increases in viral levels
and KS disease progression. A Chicago group presented information
on 27 people with KS, identified between January 1996 and October
1997. In this group, rises in HIV RNA levels (greater than ½
log increase) proceeded KS disease progression. Of the 18 individuals
who experienced a greater than ½ log increase in HIV RNA
levels, all experienced KS disease progression within two months.
The other nine individuals observed had stable HIV RNA levels and
only two of these individuals experienced KS disease progression
within the study period. This would suggest that persons with KS
who experience rises in viral levels should consider more frequent
monitoring of viral load (e.g. repeat test within a few weeks) and
consider making changes in their anti-HIV regimens. The flip side
of this coin, in this study, is that KS improvements following decreases
in HIV RNA levels were much more variable.
Commentary
Several of the studies described above suggest that we are entering
a new era in the treatment and prevention of opportunistic infections.
Although the data are not yet complete, it is becoming clear that
when HAART is successful, it has a major impact on the occurrence
of new opportunistic infections and on the need for continued maintenance
therapy for those who had such infections previously. Under the
best of circumstances, it appears that HAART results in a strengthened
immune response which is sufficiently potent to allow discontinuation
of OI maintenance therapies. Similarly, when HAART is effective,
it sometimes eliminates the need for the preventative therapies
previously employed at certain set CD4+ levels. However, how this
applies to individuals is not at all clear. Studies have not yet
provided enough information to predict who can and cannot safely
forego preventative or maintenance therapies. In theory, there may
someday be a measure of the strength of immune response which would
make it easy to know who can and cannot forego these therapies.
For now, it seems largely a matter of guess work, and thus, a decision
which comes with considerable risk.
While we lack precise knowledge on how to make decisions about
OI prevention and maintenance today, we do know a few things which
might help guide such decisions:
- First, it is clear from a number of current studies that restored
immune response is not an immediate consequence of HAART, but
rather one which develops slowly over time. Thus, it would seem
prudent for people to wait at least months to a year while maintaining
a strong HAART response before making any changes in preventative
or maintenance therapy.
- Secondly, it seems logical that the risk of withdrawing preventative
therapy would be lowest in people who never had any kind of an
OI prior to their use of HAART.
- Third, it is also logical to expect that those people who have
the strongest and best sustained immune response to HAART, as
measured by CD4+ cell increases and level, stand the best chance
of successfully foregoing OI preventative or maintenance therapy.
- Finally, an individuals tolerance for the risk of getting an
OI must be measured against each individuals tolerance for taking
additional drugs and coping with additional drug side effects.
Over time, better measures of immune response, including perhaps
tests which might predict an individuals capacity to response to
specific OIs might become routinely available. Until such time,
the issue of OI preventative and maintenance therapy will be a highly
individualistic matter, one which must be decided very carefully
by each individual and his or her physician. In extreme examples—people
with the best and worst responses to HAART—the decisions are
relatively easy to make. For those who fall between, however, it
remains a subject which must be addressed with great care. Each
significant OI, if and when it comes or recurs, has the potential
to do serious and lasting harm, as well as to derail otherwise stable
treatment with HAART.
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