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Principles of Antiretroviral Therapy
HIV infection causes progressive damage to the immune system in nearly all cases. There is NO LATENT PHASE. HIV replicates at every stage of HIV infection. The half life of an HIV virion is 6 hours. The half life of infected CD4 cell is 30 hours.
CD4 count and viral load testing are both important laboratory parameters in HIV infection, and both tests should be performed regularly.
A. The CD4-lymphocyte count is a measure of immunocompetence and disease progression.
measurements via RT-PCR or b-DNA techniques predict the rate of disease
progression. Higher viral load = higher rate of viral replication: causes more
rapid decline in CD4 count, more rapid disease progression, AND resistance to
antiretrovirals (if present)
For EVERY CD4 level, EVERY increase in viral load resulted in significant decreases in AIDS free survival.
A. Treatment should be individualized based on viral loads, CD4-lymphocyte counts, and clinical parameters.
these parameters, first and foremost is the patient’s intention to and
ability to adhere to medical therapy and follow-up including relatively
frequent laboratory examinations.
Initiation of antiretroviral therapy should be based on viral load, CD4-lymphocytes, and clinical parameters including the following:
A. Patients at low risk for progression may be monitored without therapeutic intervention including patients in these categories:
1) CD4 > 200 - 350, HIV viral load < 65,000 RT-PCR - note that providers should exercise judgment in determining whether patients in this CD4 strata would benefit from therapy
2) CD4 “high” and stable, HIV viral load < detectable RT-PCR
B. Persons with advanced HIV disease (CD4 < 200 or symptomatic disease at any CD4) almost always benefit from antiretroviral therapy. Later initiation of therapy may limit the probability of immune reconstitution that is possible with effective antiviral therapy.
initiation) versus Conservative (later initiation) approach (see below).
Currently the conservative approach to the initiation of therapy is favored by
experts and this author. Consider initiation of therapy for CD4-lymphocytes
200-350 and/or HIV viral load RT-PCR > 50,000 in asymptomatic patients. Recent
studies indicate that therapy may be safely delayed until the CD4-lymphoycte
count is approximately 200 as long as adherence to CD4-lymphocyte monitoring is
The use of potent combination therapy to suppress HIV replication below the limits of detection (optimally < 50 copies/cc) decreases or may prevent the production of mutant, drug resistant strains in the large proportion of patients treated.
A. The goal of therapy is to suppress HIV to undetectable levels, ideally < 50 copies/cc.
B. If undetectable viral load can not be achieved, the goal of therapy should be to minimize the HIV viral load. Clinical and immunologic improvement is uniformly seen at or below a HIV RT-PCR viral load of 5000 copies/cc and may also be seen at somewhat higher viral load levels.
HIV suppression below
detectable ranges does not equate with eradication. Cessation of therapy almost
always results in rebound viremia followed by loss
of CD4 lymphocytes.
The most effective means to accomplish durable suppression of HIV replication is the simultaneous initiation of combinations of effective anti-HIV drugs (HAART) with which the patient has not been previously treated and that are not cross-resistant with antiretroviral agents with which the patient has been previously treated.
Many other factors are also absolutely pivotal in a durable, completely suppressive regimen:
A. Antiretroviral choices will influence all future antiretroviral regimens and their response.
B. Maximal antiviral suppression is most rapidly and most durably achieved in patients who have not received prior therapy (and who acquired drug-sensitive strains at the time of infection)
C. Antiretroviral monotherapy is useful only in a time-limited regimen (AZT) to prevent vertical transmission and is contraindicated unless there are no other options.
D. Drugs with a low barrier to genetic resistance such as lamivudine (3TC) and the NNRTIs must ONLY be used in the company of several other potent antiretroviral drugs. In the setting of uncertain ability to adhere to medication regimens and/or in advanced disease, protease inhibitor-based regimens are probably preferred.
E. The use of only two antiretroviral drugs or of only three nucleoside reverse transcriptase inhibitors as a frontline option is discouraged but may be considered in selected circumstances when other options are not feasible. Suboptimal regimens are best used in persons with relative preservation of immunity and lower HIV viral loads (<50,000 copies/cc). Strategies with triple NRTI regimens are currently being studied.
F. Cross-resistance between antiretroviral agents should be considered at the time that a failing regimen is changed. The issues are complex and not completely understood currently. Drugs within a class are simplistically cross-resistant with all other drugs within that class.
G. When changing a regimen in someone failing therapy, resistance testing may indicate which component(s) of therapy is inactive.
H. If state-of-the-art
resistance testing and evaluation of the historical use of antiretroviral
therapy indicates that certain components of a failing regimen are
still active, these drugs may be used in subsequent regimens.
Each component of an antiretroviral regimen should be administered at optimal dosage and frequency.
A. All elements of combination therapy should be initiated simultaneously and at full dosage (exceptions are nevirapine, full-dose ritonavir — both should be dose escalated in most cases).
inhibitor serum levels and adherence to protease inhibitors may be enhanced by
co-administration of subtherapeutic doses of
ritonavir or other protease inhibitors. However, caution should be observed
with respect to toxicity and drug-drug interactions. See Guidelines.
a therapy with one drug in a combination must be interrupted, strongly
consider interrupting all the components of that regimen.
issue is clouded by the differential half-lives of components in an
antiretroviral regimen. For example, efavirenz half-life approaches 24 hours
while the half-life of zidovudine is much shorter. Anecdotally there has been
loss of activity to longer acting antiretroviral drugs after sudden,
simultaneous cessation of antiretroviral therapy. This is presumably due to
effective monotherapy with the longer-acting drug during the washout period.
Therefore, certain regimen modifications may be important prior to the cessation
of antiretrovirals if that is feasible.
Patient adherence is critical to the success of a particular regimen. An assessment of adherence should precede initiation of therapy, and it should be updated frequently and regularly. [See Adherence Section of this site.]
Due to the limited number and mechanism of action of current agents, any changes in a regimen will lead to further constraints on therapy in the future of the patient in question. Antiretroviral changes should be made cautiously. Recommendations regarding changing antiretroviral therapy include the following:
A. Therapy should not be changed prematurely. Virologic and immunologic trends should be established before medication changes are planned. See below.
B. If viral load measurements are being used to change therapy, repeat the viral load measurements prior to most, if not all, significant changes. The exception to this is the already observed trend of increasing viral load and decreasing CD4-lymphocytes with or without clinical deterioration.
C. Consideration of antiretroviral therapy change in the setting of possible virologic failure should be done in the following situations:
1) Viral load becomes detectable and continues to rise in someone who had previously had an undetectable viral load (in the absence of factors known to transiently increase viral load such as intercurrent infection or vaccination)
2) Viral load rises progressively in someone who had not achieved “complete” viral load suppression.
3) Known and unacceptable toxicity to a single agent in a regimen may be eliminated by substitution of another agent with a differing toxicity profile.
D. Consideration should be given to the following variables prior to changing therapy
1) Adherence issues: toxicity, pill burden and scheduling impact on patient, missed doses and reasons for missing, past adherence to other medications, mood, intelligence, support systems, substance use/abuse/dependency, availability of medications, methods of enforcing medication compliance, patient attitude toward need for hydration, antidiarrheals, or other “antidotes”
2) Genotypic and phenotypic resistance and cross-resistance issues
3) Pharmacokinetic issues: drug-drug interactions, disease-drug interactions or drug compartment penetration issues, malabsorption from diarrhea, nausea and vomiting, poor food-drug planning, diarrhea, hypochlorhydria, gastroenteritis
4) Toxicity issues of prior and planned antiretroviral regimens
5) Availability: Assessment of availability of continuous supplies of current and planned antiretrovirals
Assessment of need for and availability of hydration,
antidiarrheals, or other antidotes for side effects of antiretrovirals.
Consideration for availability of bathroom facilities should be included in
Women should receive optimal
antiretroviral therapy regardless of pregnancy status. However, certain
antiretroviral drugs may pose hazards to the fetus, particularly efavirenz.
Women who are using inadequate birth control or who desire to become pregnant
should not be treated with efavirenz.
The same principles of antiretroviral
therapy apply to HIV-infected children, adolescents, and adults, although the
treatment of HIV-infected children involves unique pharmacologic,
virologic, and immunologic considerations.
Persons identified during acute primary
HIV infection should be considered for treatment with
combination antiretroviral therapy to suppress virus replication to levels
below the limit of detection of sensitive plasma HIV RNA assays.
(verbatim). However, this recommendation has been called into
question by recent studies made public in 2004. Once again, the
decision to treat during primary infection should be individualized.
HIV-infected persons, even those whose
viral loads are below detectable limits, should be considered infectious.
Seminal fluid and vaginal secretions are known to harbor actively replicating
virus in a significant number of patients with undetectable serum HIV viral
loads. Therefore, they should be counseled to avoid sexual and drug-use
behaviors that are associated with either transmission or acquisition of HIV and
other infectious pathogens. In general, effective treatment does lower
the potential for transmission.
|All patients with advanced AIDS should
be directly cared for or consulted on by a physician experienced in HIV care
at some point. This consultant or primary provider should be seeing a
sufficient number of HIV patients to maintain his/her expertise.
According to the literature, this increases the survival of the patient.
For the official version of these recommendations, go to: http://aidsinfo.nih.gov/guidelines/
|Click HERE for Practical Antiretroviral Management Recommendations
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