Slide 2
During this presentation:
- I will review the natural history of HIV in the absence of therapy
- I will discuss the benefits of antiretroviral therapy and the
general principles regarding its use
- I will discuss considerations related to starting antiretroviral
therapy, especially in resource-poor settings
- I will review the possible adverse effects and drug interactions
associated with antiretroviral therapy; and finally,
- I will discuss the limitations and barriers to successful HIV
treatment with the use of current antiretroviral medications.
Slide 3
Within a few weeks after infection with HIV, there is a the rapid rise
in the concentration of HIV virus in the blood, shown in the purple line.
Slide 4
This period of viremia is accompanied by a decline in the number of
CD4-positive lymphocytes, or CD4 cells, shown in the orange line.
Slide 5
The high levels of virus in the blood lead to the development of an
HIV-specific immune response, which brings the infection under some degree
of control. This leads to a decrease in the concentration of virus,
measured as HIV RNA and referred to as the viral load, which usually
results in a rise in CD4 cell count.
The viral load following resolution of acute viremia is known as the
"viral setpoint"; it reflects the strength of the primary immune
response and varies among individuals. Those with a higher viral setpoint
have a more rapid decline in CD4 cell count, while those with lower viral
setpoints may remain immunologically stable for a longer period of time.
Although HIV-infected individuals do not usually experience symptoms
for years after initial infection, the virus continues to multiply at a
high rate throughout the course of infection in the absence of treatment,
with approximately 10 billion viral particles produced each day. This
causes progressive destruction of CD4 cells and progressive damage to the
immune system. Measurement of the CD4 cell count is used throughout the
course of HIV infection to measure the extent of immune system damage.
Measurement of viral load in the plasma reflects the activity of the virus
and is predictive of the risk of disease progression and death. Because
the virus is present in the blood and genital secretions throughout the
course of HIV infection, HIV-infected individuals are infectious even when
they have no symptoms or physical signs of infection.
Slide 6
This graph shows that the likelihood of developing AIDS in the absence
of treatment is related both to the viral load and the CD4 cell count. The
highest rates of progression to AIDS occur in individuals with high viral
loads and low CD4 cell counts, indicating high levels of plasma virus and
a damaged immune system. The lowest risk of progression to AIDS is in
those with low viral loads and high CD4 cell counts.
Slide 7
There are many benefits to using antiretroviral therapy. It helps to
stabilize the immune system, reversing the progressive destruction of
immune function and increasing the CD4 cell count. Because the development
of opportunistic infections is associated with severe damage to the immune
system and very low CD4 cell counts, these infections should be prevented
with antiretroviral therapy. If the infections are already present, their
course may be shortened or made less severe with antiretroviral therapy.
In the US and Europe, antiretroviral therapy has reduced
hospitalizations for treatment of HIV-related infections, and the death
rate from AIDS has been dramatically reduced. Brazil, a country with a
large number of HIV-infected individuals but limited resources, has
reported an 80% decrease in HIV-related hospitalizations and a 40-70%
reduction in AIDS deaths since introducing antiretroviral therapy. This
reduction has resulted in a cost savings of 677 million U.S. dollars.
Improvement in morbidity and mortality have also been seen with the
introduction of antiretroviral therapy in other developing countries
including Thailand, Senegal, and Uganda. The quality of life of
HIV-infected individuals has improved with therapy, and their hope is
restored. Antiretroviral therapy has been associated with major reductions
in mother-to-child transmission in the developed world, and, by lowering
the amount of virus in the blood, it is expected that other forms of HIV
transmission may be reduced as well. Antiretroviral therapy has been shown
to benefit both adults and children. The availability of therapy may be an
incentive for voluntary HIV counseling and testing, which increases
identification of HIV-infected individuals, allowing them to access
healthcare and prevent further transmission.
Slide 8
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,
also known as ZDV or AZT, 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 9
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 10
The third class of antiretroviral agents is the protease inhibitors or
PIs. There are currently six protease inhibitors approved for use in the
United States. Ritonavir is usually used at low doses to increase drug
levels of other protease inhibitors, since 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 11
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 is the most common reason for failure of therapy.
Slide 12
Measuring the CD4 cell count and viral load at intervals during
treatment helps to determine whether treatment is successful. Once ARV
treatment is started, long-term therapy, possibly life-long, is needed.
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.
Slide 13
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 (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 14
Before starting antiretroviral therapy, each individual should receive
a careful evaluation. The clinical stage of infection, including past or
current HIV-related illnesses that may require additional treatment,
should be assessed with a careful history and physical examination. It is
also important to identify other co-existing medical conditions, such as
chronic hepatitis, that may affect the choice of drugs and the risk of
adverse effects. All current medications, including herbal or traditional
remedies should be listed. The clinician should discuss sexual and
drug-related risk behaviors, as well as the importance of using condoms to
prevent further transmission. Although antiretroviral therapy may decrease
the risk of transmission of HIV to others, it does not eliminate that
risk. HIV may still be transmitted, even if the viral load is suppressed
below detectable levels. In women who are about to start therapy, the
clinician should take a careful menstrual history and should ask about the
use of contraception. It is important to rule out the possibility of
pregnancy and to assess the ongoing risk of pregnancy because this may
affect the choice of drug regimen. Finally, it is critical to assess the
patient's readiness to start therapy and her commitment to taking these
medications correctly and consistently, possibly for the rest of her life.
Slide 15
The choice of the initial antiretroviral regimen should be
individualized whenever possible. Consider the following factors relating
to the agents and regimens available before starting therapy: the strength
of the data on effectiveness; the potential for serious adverse events and
toxicity; side effects and tolerability, and convenience issues such as
pill burden, dosing frequency, and food and refrigeration requirements;
the potential for interaction with other drugs; the potential for
treatment options should the initial drug combination fail; and the cost
and accessibility of antiretroviral drugs.
Slide 16
In addition, there are several patient-related factors that will also
affect the choice of regimen: the stage of disease; the likelihood of
adequate adherence; the presence of pregnancy or the risk of becoming
pregnant; the presence of concurrent tuberculosis and other illnesses; and
the ability of the patient to return for regular, reliable follow-up
visits.
Slide 17
This slide lists the current WHO recommendations for initial ARV
regimens in HIV-positive adults and adolescents living in limited-resource
settings. 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.
Slide 18
Some experts have advocated the use of dual-nucleoside regimens in
limited-resource settings. These regimens are less costly, are generally
well tolerated, have a lower pill burden compared to most other regimens,
and are associated with fewer serious adverse effects than regimens that
also contain an NNRTI or a protease inhibitor.
However, it has been well established that dual-nucleoside combinations
reduce the viral load only partially, and for a limited period of time.
They are therefore associated with the inevitable emergence of nucleoside
analog drug resistance. Therefore, the use of dual-nucleoside therapy may
result in the need for more complex and difficult regimens after failure
of the initial regimen, since resistance may eliminate the nucleoside
analogs as options for future therapy. In conclusion, these regimens are
not recommended for either resource-rich or resource-poor settings.
Slide 19
Once an HIV-infected woman has started taking antiretroviral therapy,
she should be monitored for evidence of the effectiveness of therapy.
Clinical signs or symptoms that the regimen is working may include weight
gain, resolution of oral thrush, or resolution or reduced frequency of
other infections. Laboratory evidence of successful treatment includes
increase in CD4 or total lymphocyte counts and suppression of viral load,
preferably to undetectable levels.
Slide 20
Individuals on antiretroviral therapy must also be monitored for
evidence of adverse effects or toxicity. Some of the clinical signs or
symptoms suggesting possible adverse effects include rash, jaundice,
abdominal pain, or numbness or pain in the extremities. Significant
toxicity may be detected through laboratory testing, even when signs or
symptoms are absent.
Ideally, after starting antiretroviral therapy, an individual should be
seen approximately 1 month later and then every 3-4 months for clinical
assessment and laboratory testing, if needed. In patients on a nevirapine-containing
regimen, liver enzymes should be measured if possible after 2 weeks of
therapy due to concerns about liver toxicity.
Slide 21
This slide shows the types of laboratory tests that are used to monitor
ARV use. The absolute minimum laboratory tests to have before starting
antiretroviral therapy are HIV antibody test to document the presence of
HIV infection and a hemoglobin or hematocrit level to screen for anemia
before starting ZDV-containing regimens.
Basic tests are needed to provide effective monitoring of most
antiretroviral regimens. These include a white blood cell count and
differential to measure the total lymphocyte count and assess decreases in
white blood cells, which may occur from bone marrow suppression with ZDV;
measurement of liver enzymes such as serum alanine or aspartate
aminotransferase, to assess possible hepatitis co-infection and to monitor
for hepatotoxicity; serum creatinine and/or blood urea nitrogen to assess
baseline renal function and possible renal toxicity, which can occur with
indinavir treatment; serum glucose with PI-containing regimens, because
these have been associated with hyperglycemia and even overt diabetes; and
pregnancy tests for women.
Desirable tests, though not essential, include CD4 cell count,
bilirubin, amylase and serum lipids, such as triglycerides and
cholesterol. CD4 cell counts are the best indicator of immune system
response to treatment. PIs can cause lipid elevations. Extremely high
triglyceride levels may occasionally be seen and may place the patient at
increased risk for pancreatitis, which causes elevations in amylase
levels. Elevations in bilirubin can be seen with indinavir and may also
indicate liver damage with other antiretroviral agents.
Other laboratory testing may be needed when indicated by clinical signs
or symptoms suggesting toxicity. Viral load testing is currently
considered optional because of cost and limited availability.
Slide 22
Although effective antiretroviral therapy can significantly reduce
morbidity and mortality related to HIV, toxicity is not uncommon and may
be serious or severe. Use of drugs with similar toxicities should be
avoided when possible. Some toxicities are mild or transient and disappear
or diminish with continued treatment. Several ARV agents, such as the
buffered formulation of didanosine or ddI, lopinavir/ritonavir, saquinavir
and nelfinavir, commonly result in gastrointestinal symptoms such as
nausea or diarrhea. Although not serious, these side effects may result in
decreased adherence to therapy and may increase risk for dehydration in
tropical settings. Other adverse effects are potentially life-threatening
and require discontinuation of the drug. Some serious adverse effects of
antiretroviral agents apply to entire drug classes, but others are
specific to certain drugs. All of the nucleoside analogs have been
associated with an increased risk of lactic acidosis and fatty liver.
Lactic acidosis often presents with nonspecific signs and symptoms,
including fatigue, weakness, loss of appetite, nausea and vomiting.
However, it can progress to abnormal heart rhythms, multi-organ failure,
and death. Nucleoside analogs also may cause loss of subcutaneous fat,
known as lipoatrophy. Zidovudine can cause bone marrow suppression and
result in anemia and other abnormalities reflected in an abnormal complete
blood count. ZDV has also been associated with the occasional development
of myopathy, presenting with pain and aching in muscles. Both didanosine
or ddI and zalcitabine or ddC can cause potentially life-threatening
pancreatitis and these two drugs and stavudine or d4T can result in
neuropathy, presenting with numbness, tingling, or pain in the
extremities. Stavudine has also recently been associated with the rare
occurrence of ascending motor weakness, similar to the Guillain-Barre
syndrome and often accompanied by lactic acidosis. Zalcitabine has also
been associated with occasional occurrence of oral ulcers. Abacavir can
cause a hypersensitivity reaction in a small percentage of patients
usually occurring in the first six weeks of therapy. This reaction
typically presents with fever, muscle aches and other flu-like symptoms,
and sometimes with a rash. Patients who experience this reaction should
stop the drug and never take it again, as there have been deaths in
patients who took abacavir again after having experienced a
hypersensitivity reaction.
Slide 23
All of the NNRTIs can cause a skin rash. In most cases the rash is mild
and resolves with continued use of the drug, but in rare cases it can be
severe and even life-threatening, especially in patients taking nevirapine.
The NNRTIs can also cause liver toxicity, including drug-induced
hepatitis, which can sometimes be life-threatening.
Efavirenz has been associated with disturbing dreams, dizziness, and
difficulty with concentration, but these symptoms tend to decrease with
duration of therapy.
Slide 24
Protease inhibitors can cause hyperglycemia and diabetes, elevations in
serum lipids, and liver toxicity. They are also associated with changes in
body fat distribution, including both fat accumulation and loss of
subcutaneous fat.
Indinavir increases the risk of kidney stones. Patients must drink
large amounts of water to avoid this complication, especially if they live
in areas with hot climates. Amprenavir is the protease inhibitor most
likely to cause a hypersensitivity rash. The combination of lopinavir and
ritonavir has been associated with pancreatitis, which is potentially
fatal. It should be noted that any protease inhibitor can cause
pancreatitis as a result of its effects on triglycerides.
Slide 25
Many of the antiretroviral agents interact with other drugs. These drug
interactions are of clinical importance if they increase the likelihood of
drug toxicity or if they decrease the therapeutic effectiveness of an
administered drug. Significant drug interactions may be seen between
different antiretroviral agents, with other prescribed or nonprescribed
drugs, or with herbal or traditional treatments. There can also be
interactions between antiretroviral agents and certain foods or with
certain illicit drugs.
Slide 26
There are a number of drug interactions that are especially important
in limited-resource settings. Rifampin, used to treat tuberculosis, should
not be used in combination with protease inhibitors or with NNRTIs except
for efavirenz. Several of the protease inhibitors and NNRTIs also decrease
the concentration of ethinyl estradiol in oral contraceptive pills and
therefore may decrease the effectiveness of oral contraceptives. It is
recommended that women on antiretroviral regimens containing these
specific drugs should use an additional or alternative method of
contraception. Individuals who are taking anticonvulsants may have a
decrease in the levels of protease inhibitors or NNRTIs. This may increase
their risk of treatment failure and may promote the development of
resistance. Cotrimoxazole, hydroxyurea, isoniazid, and dapsone, all
commonly used in HIV-infected individuals, have toxicities that overlap
with those of several antiretroviral agents; taking these medications
together may increase the risk of serious adverse effects.
Slide 27
Antiretroviral therapy does not always work. It may be successful at
controlling HIV infection for a period of time, but may eventually fail.
Failure may be detected clinically by noting evidence of clinical
progression of disease, such as weight loss, oral thrush, or development
of a new opportunistic infection. Laboratory testing can detect failure
much earlier than can be seen from observing clinical signs or symptoms.
With effective antiretroviral therapy, CD4 cell counts generally increase,
often more than 100 cells/mm3 in the first 6-12 months of treatment. A
return to pre-treatment CD4 baseline or a decrease of greater than 30%
from the peak CD4 cell count is an indicator of treatment failure. The
most sensitive measure of treatment failure is the viral load test. If the
viral load is not suppressed to undetectable levels after at least 6
months on therapy, the therapy is generally considered to be failing. When
viral load measurement is available, it should be used as the basis for
decisions about changing therapy. In general, because other illnesses or
immunizations may cause a temporary increase in viral load and decrease in
CD4 count, these tests should not be ordered during acute illness or
shortly after an immunization. Ideally, when there are no clinical signs
of failure, the viral load and CD4 count should be repeated before a
change in treatment regimen is made to make sure the initial results are
confirmed, since they may be somewhat variable. If evidence of treatment
failure is confirmed, a change in therapy is needed to continue control of
HIV.
Slide 28
There are a number of factors that may contribute to antiretroviral
failure. The use of ineffective regimens, such as use of a single agent or
a dual-nucleoside combination, may provide temporary benefit but will
ultimately fail because they do not adequately suppress viral load for a
sustained period of time.
An effective regimen also may fail if it is given or taken at
suboptimal doses. A variety of generic antiretroviral agents are now
available in limited-resource settings and are much less expensive than
standard agents. It is important, however, to ensure that these drugs are
equal in quality and potency to the standard drugs. If a generic drug is
used that is not as potent as the standard drug, the therapy may fail and
resistance may occur. Suboptimal drug levels may also be caused by drug
interactions between antiretroviral agents and other medications,
malabsorption due to diarrhea or intestinal parasites, nausea and
vomiting, or for other reasons. Perhaps the most common cause of
suboptimal drug levels is non- adherence to therapy.
Slide 29
Finally, interruptions in treatment play a major role in treatment
failure. The high cost of antiretroviral therapy has been well publicized.
In the United States an effective regimen costs an average of
$10,000-12,000 per year per person. There are many programs in several
different countries that will make treatment more affordable to the people
who need it. However, it is critical that individuals who start therapy do
not miss doses or delay getting refills due to concerns about cost. It is
also critical to ensure a continuous supply of drugs to prevent treatment
interruptions.
Side effects and drug toxicity are common reasons for temporary
treatment discontinuation. Lack of proper adherence to treatment is the
most common reason for treatment failure. Improper adherence is common,
especially in patients taking complex regimens requiring a large numbers
of pills, difficult dosing requirements and food restrictions. Some
regimens are much easier to take than others, but it is still easy to
forget or miss doses if the patient is afraid that others Because
adherence to therapy is so important to the success of treatment with
antiretrovirals, patients need to be counseled before starting and
throughout the course of treatment about the importance owill find out he
or she is infected.
Slide 30
This study shows the important role that adherence plays in the success
or failure of antiretroviral therapy. Failure, as measured by lack of
sustained reduction in viral load, is directly related to the proportion
of prescribed doses taken. To achieve the best outcome possible,
individuals taking therapy in this study needed to take over 95% of their
doses correctly.
Slide 31
Because adherence to therapy is so important to the success of
treatment with antiretrovirals, patients need to be counseled before
starting and throughout the course of treatment about the importance of
taking their medications correctly. It is critical that individuals be
ready and able for this ongoing commitment before they start. Patients
should be educated about possible side effects and toxicity -- including
how to recognize signs and symptoms, particularly those that may indicate
serious adverse reactions. They should be counseled about how to manage
minor side effects, as well, since side effects are such a common reason
for not adhering to therapy.
Slide 32
At each follow-up visit, adherence and barriers to adherence should be
assessed. The healthcare provider should work with each patient to develop
a concrete dosing plan individualized to the patient's specific regimen,
including how it will fit in with meals and other activities in the
patient's daily schedule. Family and friends should be recruited to
provide additional support to the patient. The healthcare provider must
also provide ongoing support and encourage 100% adherence at each clinical
visit. Finally, an uninterrupted supply of antiretroviral drugs must be
ensured to obtain an optimal and lasting response to therapy and to
minimize the risk of drug resistance.
Slide 33
There are many reasons to consider changing an antiretroviral regimen
including intolerance of the regimen leading to poor adherence; drug
toxicity; the development of active tuberculosis or pregnancy; and
treatment failure. If the patient is responding well to therapy but
develops toxicity specifically associated with a single drug, that drug
may be changed to another antiretroviral agent without compromising
effectiveness or having to change the entire regimen. However, if the
reason for change is treatment failure, the entire regimen usually must be
changed. If viral load testing is available and being used to define
treatment failure, changes in the regimen can be made to
"intensify" therapy without having to change the entire regimen.
If a temporary interruption in therapy is needed to permit resolution of
toxicity, all antiretroviral agents should be stopped at the same time to
prevent the development of drug resistance. Women who become pregnant or
who are likely to become pregnant should be changed from efavirenz to
another drug, usually nevirapine. Patients who develop active TB on ARV
therapy will need a change in regimen if they are to be treated with
rifampin and are taking ARV drugs that interact with rifampin.
Slide 34
The second-line ARV regimen after failure of the initial regimen will
need to use drugs that are still active against the patient's virus
strain. Ideally, this regimen will include at least three new drugs with
at least one from a new drug class to increase the likelihood of treatment
success and minimize the risk of cross-resistance. Cross-resistance means
that resistance to a single drug may also confer resistance to other drugs
within the same class and may make a drug the patient has never taken
ineffective as well. When this happens, the number of effective treatment
options is dramatically reduced. Eventually, there may be no regimen
capable of suppressing the patient's virus. The likelihood of
cross-resistance varies among the different classes, with high likelihood
of cross-resistance among NNRTIs, high to moderate likelihood among PIs.
NRTI cross-resistance is an increasing concern. This table lists the
second-line antiretroviral regimens to consider after failure of the
initial regimen and takes into account these issues.
Slide 35
Many patients who are candidates for antiretroviral therapy have active
tuberculosis or TB, or they may develop TB while on antiretroviral
therapy. We have already discussed the issue of drug interactions between
some antiretroviral agents and rifampin, which can result in
subtherapeutic drug levels of the antiretroviral drugs. There is also the
theoretical concern that use of nevirapine may magnify the risk of liver
toxicity with TB treatment. Another issue is when to start antiretroviral
therapy in patients with both HIV and TB. TB treatment with directly
observed therapy should be started promptly after diagnosis of active TB.
For individuals who have evidence of advanced HIV infection with
extrapulmonary TB or CD4 cell count below 50/mm3, antiretroviral therapy
should be started as soon as the TB therapy is tolerated because they are
at high risk for HIV disease progression and death. In those with TB and
CD4 cell counts between 50 and 200/mm3 or with total lymphocyte counts
less than 1000-1200/mm3, antiretroviral therapy should be given after the
first 2 month intensive phase of TB treatment is completed, when the
toxicity of TB treatment is greatest. For other HIV and TB co-infected
patients, consideration should be given to delay antiretroviral therapy
until TB treatment is completed. In this situation, standard drug regimens
for both diseases can be utilized and drug toxicity is less.
When antiretroviral therapy is started early in the course of TB
treatment, TB symptoms can gradually worsen for 2-3 weeks after beginning
antiretroviral therapy. This is referred to as the immune reconstitution
syndrome, and resolves on its own. In general, antiretroviral therapy
should be continued without interruption.
Slide 36
Protease inhibitors and NNRTIs should be used with caution in people
with chronic liver disease because they may increase the risk of serious
liver toxicity. Several of the protease inhibitors may worsen symptoms in
patients who already have chronic diarrhea. In patients with renal
insufficiency, indinavir should be avoided and the doses of zidovudine,
lamivudine, stavudine and didanosine should be adjusted. Because
zidovudine can cause bone marrow suppression, it must be used with caution
in individuals with anemia.
Slide 37
When considering the use of antiretroviral therapy, it should be
remembered that it is not a cure for HIV/AIDS and that elimination of HIV
from the body has not been achieved using even the most powerful therapies
available. Furthermore, HIV can still be transmitted, even when an
individual is on therapy and when the viral load is undetectable.
Slide 38
In summary, antiretroviral therapy can significantly reduce morbidity
and mortality related to HIV. However, for therapy to be effective,
antiretroviral agents must be used in combination and must achieve a
sustained decrease in viral load to below detectable levels. Decisions
about antiretroviral therapy are complex and require consideration of
potential adverse effects, drug interactions, resistance issues and the
need for proper adherence.
