Slide 2
The objectives of this presentation are to:
- Discuss issues to consider when using antiretroviral therapy in
pregnant women
- Review clinical trials that show the effectiveness of antiretroviral
drugs in reducing mother-to-child transmission or MTCT
- Describe recommended antiretroviral regimens, and - Discuss
implications of resistance to antiretroviral therapy during pregnancy
Slide 3
A key objective when counseling all women of childbearing age,
including those with HIV, is to make effective contraception available to
reduce the likelihood of unintended pregnancy.
For all HIV-positive women of childbearing age and women of unknown HIV
status, especially in high HIV prevalence areas, it is important to
discuss childbearing desires and issues related to HIV during pregnancy,
including the risk of MTCT and possible interventions to reduce this risk
so that these women can make informed decisions about whether or when to
become pregnant. In areas with high HIV prevalence, discussing some of
these issues with women of unknown HIV status may promote voluntary HIV
counseling and testing before pregnancy.
When considering initiation of antiretroviral therapy in HIV-positive
women who may become pregnant, the choice of specific agents should take
into account the possibility that antiretroviral drugs may be received
during the early first trimester, before pregnancy is recognized and
during the primary period of fetal organ development. Women may become
pregnant while on antiretroviral therapy because they want to conceive or
because they are not using or are inconsistently using effective methods
of contraception. For these women, antiretroviral agents that may be toxic
to the developing fetus should be avoided.
Slide 4
It is estimated that 600,000 newborns with HIV infection are born each
year. These children were born to HIV-positive mothers and were infected
at some time during pregnancy, childbirth, or breastfeeding. Most of these
new infections occur in limited-resource settings, and most of these
children will die before they reach adolescence.
This graph is based on the Centers for Disease Control and Prevention
or CDC surveillance data for perinatally acquired AIDS cases from 1985
until 1999 in the U.S. Since 1992, there has been greater than 80%
reduction in pediatric AIDS incidence in the U.S. This decline has
coincided with the increasing use of antiretroviral therapy during
pregnancy beginning with the reporting of results from the Pediatric AIDS
Clinical Trials Group or PACTG 076 clinical trial.
The PACTG 076 study was the first clinical trial to examine the
effectiveness of antiretroviral drugs in reducing MTCT. In this trial,
zidovudine, also known as ZDV or AZT, was the only drug used. In early
1994, this study was stopped prematurely after an interval evaluation of
results found a dramatic difference in MTCT rates between ZDV and placebo
recipients. There was about a two-thirds reduction in transmission among
those who received ZDV compared to those who received placebo. These
results were rapidly translated into public health policy and clinical
practice in the U.S. and western Europe.
Slide 5
There are two primary goals for using antiretroviral therapy during
pregnancy. The first is to treat HIV infection in the woman herself.
Indications for starting antiretroviral therapy during pregnancy to manage
maternal infection are the same as those for nonpregnant adults and
adolescents with HIV. These indications are discussed in more detail in
the tutorial entitled Antiretroviral Therapy. The second goal is to
prevent transmission to the fetus or newborn.
Slide 6
There have always been concerns about the use of various
pharmacological agents in pregnant women, specifically about the effects
of in utero and newborn drug exposure. These concerns have also been
raised about the use of antiretroviral agents during pregnancy. However,
in general, the goals of improved maternal health and improved child
health are not in conflict. The basic principle that should be used in
treating pregnant women is that therapies of known benefit to the woman
should not be withheld during pregnancy unless the risk of adverse effects
to the mother, fetus or newborn outweighs the expected benefit to the
woman.
Slide 7
Antiretroviral drugs that are currently available in the United States
and approved by the US Food and Drug Administration fall into three
classes. The first class consists of the nucleoside and nucleotide reverse
transcriptase inhibitors, listed on this slide. These include zidovudine,
which was the first antiretroviral agent developed. There are also
currently two medications that combine two or three nucleoside reverse
transcriptase inhibitors in a single formulation.
Slide 8
The second class of drugs is the non-nucleoside reverse transcriptase
inhibitors or NNRTIs. This class includes nevirapine, which has been shown
to significantly reduce the risk of mother-to-child transmission of HIV.
Slide 9
The third class of antiretroviral agents is the protease inhibitors or
PIs. There are currently six protease inhibitors approved for use in the
US. Ritonavir is usually given at low doses to increase drug levels of
other protease inhibitors, because it is hard to tolerate at high doses.
The most recently approved protease inhibitor is a combination of a low
dose of ritonavir with another protease inhibitor, lopinavir.
Slide 10
There are special considerations for the safe and effective use of
antiretroviral drugs during pregnancy. The first consideration is
pharmacokinetic issues. Some drugs behave differently in pregnant women
than in nonpregnant women due to increased plasma volume during pregnancy
and differences in absorption, metabolism, and excretion. The placenta
itself may also play a role in transformation of drugs. These physiologic
changes mean that some drugs may need to be given at different doses
and/or different frequencies during pregnancy for effects equal to those
in nonpregnant individuals. They could also mean that pregnant women might
be more susceptible to drug toxicity if they are given in standard doses.
Less than half of the antiretroviral agents that are currently available
have been studied in pregnant women. For drugs in the nucleoside reverse
transciptase inhibitor class, which includes ZDV, the dose given to
pregnant women should be the same as the dose given to nonpregnant women
for these agents. Data is more limited about appropriate dosing for other
antiretroviral agents. In several phase I studies, levels of PIs that have
been studied in pregnant women appear to be lower than those observed
postpartum, but final dosing recommendations are not yet available and
dosing according to standard guidelines is currently recommended. The
second consideration is maternal safety and toxicity issues. There are
known adverse effects associated with use of specific antiretroviral
drugs. Some of these may be more common in women and could be potentially
influenced by pregnancy. The third consideration is fetal safety and
toxicity related to antiretroviral exposure. The effect of a drug
administered to the mother on the fetus or newborn is dependent on its
ability to cross the placenta or to cross into breast milk. The fourth
consideration is the effectiveness of the drugs in reducing
mother-to-child transmission. The fifth consideration is related to
concerns about the development of antiretroviral drug resistance if a
single antiretroviral agent is used alone to prevent MTCT or if an
effective combination of antiretroviral agents is not taken correctly and
consistently. The last major consideration is the woman's stage of disease
and her own need for antiretroviral therapy. As already mentioned, the
indications to use antiretroviral regimens to treat HIV-positive pregnant
women are the same as those for other HIV-positive adults. These are
discussed in more detail in the Antiretroviral Therapy tutorial. It is
important to remember that a healthy mother is one of the most important
factors in ensuring that a child will be healthy as well. These drugs can
reduce mortality and morbidity and prolong and improve the life of the
woman. Now, I'll talk about a few of these considerations in more detail.
Slide 11
Antiretroviral drugs have been associated with a variety of adverse
effects, some of which are mild and resolve without treatment and others
which are more serious and possibly even life-threatening. Some serious
adverse effects of antiretroviral agents apply to entire drug classes,
while others are specific to certain drugs. Pregnant women are at risk for
the same adverse effects with antiretroviral drugs as nonpregnant
individuals. Some adverse effects, however, may be more common in women or
have special significance during pregnancy. Certain adverse effects may be
worsened or more common during pregnancy because of physiologic changes
during pregnancy or interaction with pregnancy-related signs or symptoms.
Several antiretroviral drugs can have gastrointestinal side effects,
including the buffered formulation of didanosine or ddI, stavudine or d4T,
saquinavir, indinavir and, less commonly, ZDV. If one or more of these
drugs are given during early pregnancy to a woman who is experiencing
pregnancy-related nausea and vomiting, she may not be able to take the
drugs or absorb them sufficiently, which may increase her risk of
developing antiretroviral drug resistance. Hyperglycemia is one of the
side effects associated with the use of protease inhibitors or PIs. Some
individuals on PIs will develop glucose intolerance or even diabetes.
Pregnancy also independently predisposes women to glucose intolerance. It
is not known whether gestational diabetes is more common in pregnant women
taking PIs. Anemia is more common in women receiving ZDV, and during
pregnancy, anemia is more common because of the increase in plasma volume
and the nutritional demands of the developing fetus. Although there was no
serious hematologic toxicity observed in African clinical trials using ZDV
during pregnancy and the anemia was generally mild, this adverse effect is
of concern in areas with higher baseline rates of maternal anemia related
to poor nutrition and high rates of malaria and parasitic diseases.
Slide 12
There are three serious adverse effects that may be increased in
frequency in women. Lactic acidosis is a rare life-threatening condition
associated with nucleoside reverse transcriptase inhibitor or NRTI use. In
2001, three maternal deaths were reported in the U.S. in women who had
been on long-term combination antiretroviral therapy including stavudine
or d4t and didanosine or ddI. It is not clear whether pregnant women are
at increased risk for lactic acidosis. It is also possible that the
initial signs and symptoms of lactic acidosis, which are nonspecific and
include fatigue, weakness, loss of appetite, and nausea and vomiting, can
be missed or confused with other pregnancy-related symptoms or conditions
like acute fatty liver or severe preeclampsia. However, without
intervention, this condition can progress to abnormal heart rhythms,
multi-organ failure, and death. Pancreatitis is a serious and potentially
life-threatening condition that has also been associated with the use of
the NRTI class of drugs, especially ddI and zalcitabine or ddC.
Pancreatitis was present in two of the three maternal deaths from lactic
acidosis. Liver toxicity or damage has been associated with ongoing
nevirapine use, but has not been reported in women who have received a
single dose of nevirapine during labor to reduce the risk of MTCT.
HIV-infected women who are receiving antiretroviral therapy during
pregnancy for treatment of maternal disease as well as for prevention of
MTCT, should receive careful and regular monitoring for possible toxicity.
Clinical and laboratory monitoring for toxicity are discussed in detail in
the tutorial entitled Antiretroviral Therapy.
Slide 13
Concerns about fetal and newborn safety and toxicity related to
antiretroviral therapy apply both to infected and uninfected but
antiretroviral-exposed babies. The risk of harm to the fetus or newborn
likely depends on the specific drug or combination of drugs, doses,
gestational age, duration of exposure, interaction with other drugs, and
possibly the genetic make-up of the fetus or newborn. Information about
the safety of antiretroviral drugs during pregnancy comes from animal
toxicity data, clinical experience, reports to the Antiretroviral
Pregnancy Registry, and from clinical trials. The Antiretroviral Pregnancy
Registry is a collaborative project of the pharmaceutical manufacturers of
antiretroviral drugs, and obstetric and pediatric healthcare providers and
is designed to collect observational experience on antiretroviral exposure
during pregnancy to assess the possible risk of teratogenicity or birth
defects with these agents. Information is limited for antiretroviral drugs
because of their recent development and use during pregnancy. ZDV was the
first antiretroviral drug to be developed and introduced into clinical
care, therefore, it is the drug with the most information about use during
pregnancy. The data that exists is reassuring. There has been no evidence
of increased risk for congenital abnormalities. There have also been no
differences in growth, neurodevelopment, or immune function in babies born
to HIV-positive mothers exposed to ZDV as compared to unexposed children.
The only antiretroviral agent at this time with evidence concerning for
teratogenicity in humans is efavirenz, a powerful antiretroviral agent
from the NNRTI class of drugs. In primate studies, efavirenz was
associated with serious birth defects, including anencephaly,
microphthalmia, and cleft palate. More recently, there has been a report
of a human newborn born with a myelomeningocele after early in utero
exposure to efavirenz. Another potential type of toxicity from
antiretroviral use is carcinogenicity or the risk of inducing cancers in
exposed children later in life. At this time, there have been no cancers
observed in children up to 6 years after in utero exposure to ZDV.
Slide 14
Anemia can be seen in newborns exposed to ZDV during gestation but is
usually mild and generally does not require treatment. In clinical trials
using ZDV for prevention of MTCT conducted in Africa, although rates of
serious anemia were higher than in other studies, ranging from 5-9%, there
was no significant difference between ZDV and placebo-exposed newborns.
The NRTI class of drugs can inhibit synthesis of mitochondrial DNA,
resulting in mitochondrial dysfunction. This condition most commonly
presents with neurological symptoms and can be life-threatening. Data from
France showed that 16 out of 2209 or 0.7% of antiretroviral-exposed
newborns had probable mitochondrial toxicity, compared to none of the 1874
unexposed newborns. Two of the antiretroviral-exposed and HIV-negative
children died due to this disorder. Subsequently US researchers reviewed
the cases of over 20,000 children born to HIV-positive women; of the 223
children who had died, none of the deaths were felt to be related to
mitochondrial toxicity. A completed clinical review of 1954 living
uninfected children from one cohort did not identify any child with
antiretroviral exposure who had symptoms consistent with mitochondrial
toxicity. Another review of children in the PETRA study, a MTCT prevention
clinical trial in Africa, identified 68 children who had neurological
symptoms. There was no difference in the occurrence of neurological
symptoms between children exposed to ZDV and 3TC, which were the
antiretroviral drugs being studied, versus placebo, and no clear cases of
mitochondrial toxicity as a cause of symptoms. In summary, mitochondrial
toxicity appears to be a possible but very rare complication associated
with exposure to NRTI agents.
Slide 15
There are several possible adverse pregnancy outcomes that may be more
common in untreated HIV-positive pregnant women. These include low birth
weight newborns, preterm delivery, and fetal or newborn death. The
possible role of antiretroviral therapy in increasing risk for these
outcomes is unclear. Experience with use of ZDV has been reassuring and no
increased risk of these adverse outcomes has been seen. There are
conflicting data as to whether combination antiretroviral therapy during
pregnancy is associated with adverse pregnancy outcomes, especially
preterm delivery.
At this time, HIV-positive women who are receiving antiretroviral
therapy during pregnancy for treatment of maternal disease, as well as for
prevention of MTCT, should receive careful and regular monitoring for
pregnancy complications.
Slide 16
A major consideration in the use of antiretroviral drugs during
pregnancy is their effectiveness in reducing MTCT. The next several slides
summarize the completed clinical trials that have at least 6 months
followup data examining the use of antiretroviral agents for prevention of
MTCT. The cost of a single course of each regimen is listed in US dollars
but is based on the cost of using generic drugs produced in Brazil. The
initial study examining the effectiveness of antiretroviral agents in
prevention of MTCT was the PACTG 076 study, in which ZDV was begun at 14
weeks of gestation and continued for the duration of pregnancy, given by
intravenous or IV infusion during labor and to the newborn for the first 6
weeks of life. This regimen resulted in a 68% reduction in transmission as
compared to placebo in a nonbreastfeeding population. However, this
regimen is expensive and complex, so it cannot be used in most
limited-resource settings. The PACTG 076 study was followed by a series of
clinical trials in developing countries testing shorter courses of ZDV or
alternative antiretroviral agents or combinations of agents. The first of
these trials was in Thailand, using only ZDV, begun at 36 weeks of
gestation through the remainder of pregnancy, given to the mother orally
during labor and not given to the newborn at all. This regimen, in a
nonbreastfeeding population, resulted in a 50% decrease in MTCT compared
to placebo and was simpler and much less expensive than the PACTG 076.
Slide 17
Another study in Thailand examined the efficacy of ZDV given in four
different schedules, beginning as early as 28 weeks gestation or as late
as 35 weeks and given to the newborn for 3 days or for 6 weeks. The lowest
transmission rates were associated with administration earlier during
pregnancy and/or longer newborn administration.
Slide 18
Other studies conducted in Africa among breastfeeding women have
examined ZDV alone or in combination with 3TC beginning late during
pregnancy, with oral administration during labor, and either no therapy to
the newborn or a short duration of newborn or mother and newborn treatment
after birth. Each of these studies showed significant early reductions in
MTCT as compared to placebo, although efficacy waned with time.
Slide 19
There have also been studies examining therapy initiated at the onset
of labor with a short course of therapy after birth to the newborn or to
both newborn and mother. The HIVNET 012 study conducted in Uganda found
that a simple and inexpensive regimen involving administration of a single
dose of nevirapine at the onset of labor to the mother and a single dose
to the newborn within 72 hours of life was associated with a significant
reduction in MTCT as compared to ZDV given during labor and to the newborn
for 1 week. More recently, an attempt to compare intrapartum and
postpartum mother and newborn dosing of ZDV and 3TC versus nevirapine
found early evidence of efficacy with both regimens and no significant
differences between the two. Additional data on the effectiveness of
antiretroviral regimens in reducing MTCT comes from observational studies.
Data from New York covering the period 1995 to 1997 showed that MTCT rates
were 10% when ZDV was started intrapartum by IV infusion and given to the
newborn for 6 weeks and 9.3% when given only to the newborn, starting
within 48 hours after delivery. The effectiveness of regimens that are not
given until the onset of labor is important in areas where attendance at
antenatal care clinics is poor and women do not present for care until
labor.
Slide 20
Several short course antiretroviral regimens have now been proven
effective in reducing MTCT in both breastfeeding and nonbreastfeeding
populations. Although newborns who are breastfed and given these regimens
have a lower rate of infection than those newborns who were given
comparison drug or a placebo, the antiretroviral drugs are less effective
at preventing MTCT in this group than in newborns who are not breastfed.
As shown in this graph, the likelihood of infection increases as the
newborns who received antiretroviral preventive therapy get older, most
likely because of more chances of infection occurring through
breastfeeding. There is no evidence that the regimens studied to date
decrease the risk of MTCT from breastfeeding. Clinical trials are
evaluating the value of continuing antiretroviral therapy for mother
and/or newborn for a longer period of time after birth, as well as
changing breastfeeding practices.
Slide 21
Antiretroviral drug resistance is a serious concern in pregnant women
and in other HIV-positive individuals. Antiretroviral drug resistance is a
major cause for failure of antiretroviral therapy and is more likely to
occur when single antiretroviral agents are administered, when ineffective
antiretroviral combinations are given, or when effective regimens are not
taken correctly or consistently. During pregnancy, there are concerns that
the development of resistance could potentially increase the risk of MTCT
during the current pregnancy or during subsequent pregnancies. In women
who have access to ongoing antiretroviral therapy for their disease, the
development of drug resistance may reduce their future treatment options.
Slide 22
Antiretroviral drug resistance is a serious concern in pregnant women
and in other HIV-positive individuals. Antiretroviral drug resistance is a
major cause for failure of antiretroviral therapy and is more likely to
occur when single antiretroviral agents are administered, when ineffective
antiretroviral combinations are given, or when effective regimens are not
taken correctly or consistently. During pregnancy, there are concerns that
the development of resistance could potentially increase the risk of MTCT
during the current pregnancy or during subsequent pregnancies. In women
who have access to ongoing antiretroviral therapy for their disease, the
development of drug resistance may reduce their future treatment options.
Slide 23
Subsequent studies have suggested that women with more advanced disease
and who are treated with ZDV alone, are more likely to develop ZDV
resistance, especially with longer durations of therapy. In a subgroup of
the Women and Infants Transmission Study, one-quarter of women with more
advanced disease who received antepartum ZDV only for maternal health
indications had detection of ZDV resistance mutations. When adjusted for
duration of ruptured membranes and total lymphocyte count, the presence of
resistance mutations conferred an increased risk for MTCT. Factors
associated with resistance in the mothers at the time of birth included
ZDV use before pregnancy, higher HIV-RNA levels or viral loads, and lower
CD4-positive cell percentage. Currently, women with these characteristics
would be advised to take highly active antiretroviral therapy or HAART
regimens for their own health and to minimize the risk of MTCT. The use of
effective HAART regimens also minimizes the risk that antiretroviral
resistance will develop. However, in settings with limited-resources,
single agent antiretroviral therapy may be the only option for helping
prevent MTCT. If additional antiretroviral agents are available and
accessible, there may be limited ability to measure CD4 count or HIV-RNA
level to determine who may need a more powerful regimen.
Slide 24
The concerns about resistance are greater with the use of nevirapine
than with ZDV because the use of an NNRTI agent alone is associated with
the rapid emergence of resistance. A single mutation can significantly
decrease drug binding causing the agent to be ineffective. In contrast,
with the use of drugs from the NRTI class, multiple mutations are required
to cause high-level resistance. An exception is with 3TC, to which high
level resistance develops with a single mutation.
Another feature of nevirapine that raises concerns about resistance is
that it has a prolonged half-life when given to women during labor and to
the newborn. This prolonged half-life could allow prolonged exposure to
subtherapeutic drug levels after a single dose, predisposing to
development of resistance.
In the HIVNET 012 study in Uganda, after one dose of nevirapine, almost
one-fifth of women had nevirapine resistance detected at six weeks
postpartum. Resistance was more likely to be seen in women who had more
advanced disease, higher viral loads and lower CD4 counts. There was no
evidence that the development of resistance increased risk of transmission
between mother and child. More than 48% of infants infected despite
receiving nevirapine prophylaxis had detectable nevirapine resistance;
this disappeared by 1 year of age. Furthermore, when resistance did
develop, specific resistance mutations were different in mothers and
infected newborns.
When retested between 1 to 2 years after childbirth, evidence of
resistance in mothers had also disappeared. The disappearance of
resistance in both mothers and infected children is not unexpected.
Resistance develops because the virus mutates to keep growing and to
escape the antiretroviral effect of the drug to which an individual is
exposed. When the antiretroviral agent is no longer present, the normal
"wild-type" viral strains again become dominant and the
resistance strains become a minority and cannot be detected. However, if
the drug to which resistance developed is reintroduced, the resistant
viral strains will re-emerge. Therefore, once a person is resistant to an
antiretroviral drug, they are always resistant to that drug. However, in
the case of very short-term intermittent therapy that is used for the
prevention of MTCT, nevirapine may still be effective in subsequent
pregnancies because it would take time for the resistant viral strains to
reemerge. It remains unclear how this regimen may affect future maternal
treatment options.
In the PACTG 316 study conducted in the US and Europe, women who were
on an existing antiretroviral regimen were given a single dose of
nevirapine in labor and a single dose was given to their newborns in order
to determine if this would result in a greater reduction in MTCT. The
addition of nevirapine was not associated with a greater reduction in MTCT
as compared to the addition of a placebo to the existing regimen. However,
in women who received nevirapine and had detectable HIV viral load at
delivery, new nevirapine resistance mutations were detected at 6 weeks
postpartum in 14 of 95 women or 15%. Therefore, in women who are on a
HAART regimen for treatment of their own disease, there is no benefit in
adding a single dose of nevirapine in labor to further reduce MTCT and
there may be added risk for developing nevirapine resistance.
Slide 25
The final consideration in the use of antiretroviral drugs during
pregnancy is the woman's stage of disease and need for antiretroviral
therapy.
The goal of antiretroviral therapy is to reduce the viral load by as
much as possible -- generally to levels that are too low to be detected --
for as long as possible, and to restore or preserve normal immune
function. To achieve this goal, antiretroviral agents must be used in
combination, in most cases using drugs from different classes. The
rationale for combination therapy of HIV infection is similar to the
strategy for treatment of tuberculosis: to prevent or delay the
development of drug resistance. There are many effective antiretroviral
combinations available, but the specific drug combination used is less
important in predicting success than the patient's ability to take the
prescribed regimen correctly and consistently. Lack of adequate adherence
to treatment often leading to antiretroviral drug resistance is the most
common reason for failure of therapy.
Slide 26
When a patient does not take the prescribed treatment regimen with
near-perfect adherence, or when the regimen is ineffective, HIV continues
to replicate and mutate despite treatment. This allows the patient's virus
to become resistant to drugs being taken. Once a patient's virus develops
resistance to a drug, that drug will no longer work. Resistance to some
drugs develops more quickly and easily than to others. Also, resistance to
one drug may cause cross-resistance to other drugs within the same class,
which means that future treatment options will also be limited.
Measuring the CD4 cell count and viral load at intervals during
treatment helps to determine whether treatment is successful. Once
antiretroviral treatment is started, long-term therapy, possibly
life-long, is needed.
Slide 27
Taking antiretroviral therapy requires a long-term commitment from the
patient. Correct and consistent use is required for the drugs to be
effective and the response to be durable or to last. Antiretroviral agents
can have side effects that can make them difficult for some patients to
take. Thus, the decision about when to start therapy is an important one.
Treating someone too early, before therapy is truly indicated, may lead to
unnecessary toxicity and premature development of drug resistance.
Antiretroviral therapy should be given to individuals with symptomatic
disease, including those with wasting, opportunistic infections, or
HIV-related cancers, recurrent or persistent oral thrush, and recurrent
invasive bacterial infections, irrespective of CD4 cell count or total
lymphocyte count. Therapy is also recommended for people with earlier
symptomatic or asymptomatic HIV infection when the CD4 cell count falls
below 200/mm3. When CD4 cell testing is not available, treatment is
recommended for earlier symptomatic infection with a total lymphocyte
count below 1200/mm3. However, in the absence of symptoms, total
lymphocyte count alone is less useful as a marker of disease severity or
progression and should not be used as an indicator to begin antiretroviral
therapy.
Anemia is common in limited-resource settings and may be related to
malnutrition, malaria or other parasitic diseases. In women, anemia may be
the result of menstruation or recent pregnancy-related hemorrhage.
Although not specifically part of the World Health Organization or WHO
staging system, anemia is also common in HIV-infected individuals and may
be due to HIV itself or to underlying opportunistic infections. Anemia has
also been shown to be an independent predictor of progression and death in
HIV-infected individuals. Therefore, anemia may be another potential
indication for antiretroviral therapy, especially if there is no obvious
cause or if it is does not respond to therapy, and the total lymphocyte
count is below 1200/mm3. For a full description of the WHO staging system,
click on the link under Resources.
Although high HIV-RNA level or viral load is associated with a more
rapid decline in CD4 cell count and more rapidly progressive HIV
infection, measurement of viral load is not considered necessary to start
therapy. A specific viral load in the absence of symptoms or low CD4 cell
count should not be routinely used as an indicator to start antiretroviral
treatment.
Slide 28
This slide lists the current WHO recommendations for initial
antiretroviral regimens in HIV-positive adults and adolescents living in
limited-resource settings, along with considerations for use in pregnancy.
All regimens include a dual nucleoside component combined with a potent
third drug, either an NNRTI, the potent NRTI abacavir or a protease
inhibitor or two protease inhibitors using low dose ritonavir to enhance
potency. Although there are other possible effective combinations, these
specific regimens were chosen taking into account toxicity, clinical
experience, and the availability of fixed dose combinations for ZDV/3TC,
and for ZDV, 3TC, and abacavir, which makes administration easier and
adherence more likely. It is important to note that ZDV and d4T should
never be used together because of proven antagonism between these two
drugs. In the dual nucleoside plus NNRTI regimens, the advantage is a low
pill burden and high effectiveness. These regimens are often better
tolerated than PI-containing regimens. Therapy with PIs can be delayed
until needed when other regimens not including protease inhibitors have
failed. NNRTI-containing regimens are also associated with short-term side
effects, including rash, liver toxicity and, in the case of efavirenz,
central nervous system symptoms. Efavirenz should not be used in pregnant
women or in women for whom effective contraception cannot be ensured
because of information suggesting an increased risk of serious birth
defects with efavirenz. Patients who have HIV-2 instead of HIV-1 infection
are not effectively treated with the NNRTI class of drugs. The ZDV/3TC/abacavir
regimen involves taking only two pills a day, and there are no significant
drug interactions. Its main disadvantages are some uncertainty about its
effectiveness with very high viral load or very advanced disease and low
CD4 cell count. Furthermore, about 3-5% of patients who take abacavir
develop hypersensitivity to this drug, and some individuals who restarted
abacavir after having had this reaction have died. The risk of abacavir
hypersensitivity in areas with a high incidence of febrile illnesses, such
as malaria and tuberculosis, could make accurate diagnosis of this
potentially fatal adverse effect more difficult. The dual nucleoside plus
PI regimens have proven to have high potency in reducing viral load to
undetectable levels. It is generally believed that use of one protease
inhibitor in a regimen may be less potent than regimens containing two
protease inhibitors, especially in individuals with more advanced disease.
However, PI-containing regimens have a high pill burden and significant
interactions with other drugs. All of these combinations, except for the
regimen containing saquinavir and ritonavir, cannot be used if the patient
is also being treated with rifampin for tuberculosis. There are also
significant short-term side effects and long-term toxicity seen with these
PI-containing regimens. The ritonavir containing regimens require
availability of refrigeration prior to dispensing, although patients do
not need to have access to refrigeration. With both PI and NNRTI-containing
regimens, resistance that develops to one of these drugs may confer
resistance to other drugs in the same class and may, therefore, compromise
future therapy with PIs or NNRTIs. NNRTIs have a lower barrier to
resistance than PIs, making almost perfect adherence essential to
long-term effectiveness. For information on dosing and schedule of these
regimens, refer to the 2002 WHO recommendations under the Resources link.
Slide 29
Although there have been no clinical trials looking at the impact of
HAART on transmission, current observational and epidemiological studies
find the lowest transmission rates in women treated with HAART, usually in
the 1-2% range.
A primary reason for this further reduction in MTCT rates is probably
because HAART is associated with the greatest suppression in HIV viral
load, which is directly correlated with the risk of MTCT. Because of the
complex issues in prescribing HAART, this should be done in consultation
with an HIV specialist.
Slide 30
Current guidelines for the use of antiretroviral drugs during pregnancy
are based on World Health Organization recommendations. Indications to
start HAART in pregnant women are the same as for nonpregnant adults. The
specific antiretroviral regimen should be chosen from among those
recommended for nonpregnant adults. However, drugs with potential toxicity
to the mother or the fetus or newborn should be avoided. Efavirenz, as we
have already discussed, was associated with serious birth defects in
primate studies and myelomeningocele in a human newborn after early in
utero exposure to efavirenz.
Amprenavir, which is in the PI class of drugs, should not be given to
pregnant women in the oral solution form, because the solution contains a
substance that cannot be metabolized during pregnancy.
Because of concerns about lactic acidosis, the combination of ddI and
d4T should be used cautiously and only if needed because of failure or
intolerance with other regimens.
ZDV is included if possible in antiretroviral regimens during pregnancy
because it has the largest experience in terms of effectiveness and
maternal and fetal safety.
Slide 31
For pregnant women who do not yet need antiretroviral therapy for their
own disease, antiretroviral drugs should be used to reduce the risk of
MTCT, if available. One of the regimens shown to be effective in reducing
MTCT should be chosen. The specific regimen used may depend on what drugs
are available and affordable. In general, the longer and more complex
regimens appear to be more effective than the simpler and shorter regimens
that start in late pregnancy or during labor. However, these simple and
shorter regimens are less expensive and are an important option for women
who present late in pregnancy or during labor and for those women who have
difficulty with adherence. For the purposes of prevention of MTCT, every
HIV-positive pregnant woman should be treated with antiretroviral agents,
if these are available. This conclusion has been reached after a
meta-analysis examined MTCT in women who had low viral loads, under 1000
copies/ml. Women who received antiretroviral therapy, usually ZDV only,
had a transmission rate of 1%, compared to a transmission rate of almost
10% when no antiretroviral therapy was given.
Slide 32
Women who are diagnosed with HIV during early pregnancy and are
candidates for HAART can generally delay starting antiretroviral therapy
until after the first trimester of pregnancy to decrease fetal exposure.
However, for women who are severely ill, the benefit of starting therapy
immediately may outweigh the theoretical risk to the fetus. Women who are
receiving antiretroviral therapy when they become pregnant can generally
continue therapy. A change in regimen should be considered if the drugs
being received include those of particular concern for fetal or maternal
toxicity, such as efavirenz or the combination of ddI and d4T, or if there
is significant intolerance to one or more drugs in the regimen that could
be worsened during pregnancy and possibly lead to poor adherence. An
option is to stop all drugs temporarily until the first trimester is over
to reduce early fetal exposure and to get past the period when morning
sickness is common. When antiretroviral drugs are stopped, there may be a
rebound in HIV viral load that could potentially increase risk of early in
utero MTCT, although transmission early in pregnancy appears to be rare.
If drugs are stopped temporarily, they should all be stopped together and
restarted simultaneously to reduce the risk of resistance developing.
Women who require antiretroviral therapy for themselves and are
breastfeeding should continue ongoing antiretroviral therapy. Based on
current information, prior administration of short course ZDV/3TC or
single dose nevirapine for prevention of MTCT should not eliminate
consideration of these agents as part of a combination antiretroviral drug
regimen for treatment of HIV in the mother.
Slide 33
A legitimate question is whether pregnant women should be the first
individuals in limited-resource settings to receive ongoing and effective
combination antiretroviral therapy to treat their HIV. HAART has been
associated with the lowest rates of MTCT and with decreased mortality and
morbidity in infected individuals. The ongoing health of the mother is key
to optimal health in newborns and young children. Some individuals have
raised the question about whether it is ethically appropriate to give
medication to prevent MTCT only when the mother will inevitably die and
leave her children as orphans.
Slide 34
In summary, - Antiretroviral therapy is associated with a reduction in
morbidity and mortality in HIV-infected individuals and should be given to
pregnant women according to standard guidelines. - Antiretroviral therapy
is associated with significant reductions in MTCT and should be used for
this purpose when therapy is not needed for maternal health indicators. -
There are special considerations for using antiretroviral agents during
pregnancy that must be considered for safe and effective use.
