Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents
ESTABLISHED HIV INFECTION
Patients who have established HIV infection are considered in two arbitrarily defined clinical categories: 1) asymptomatic infection or 2) symptomatic disease (e.g., wasting, thrush, or unexplained fever for >2 weeks), including AIDS, defined according to the 1993 CDC classification system (6). All patients in the second category should be offered antiretroviral therapy. Considerations for initiating antiretroviral therapy in the first category of patients (i.e., patients who are asymptomatic) are complex and are discussed separately in the following section. However, before initiating therapy in any patient, the following evaluation should be performed:
Additional evaluation should include routine tests pertinent to the prevention of OIs, if not already performed (i.e., VDRL, tuberculin skin test, toxoplasma IgG serology, and gynecologic exam with Pap smear), and other tests as clinically indicated (e.g., chest radiograph, hepatitis C virus [HCV] serology, ophthalmologic exam) (AII). Hepatitis B virus (HBV) serology is indicated for a patient who is a candidate for the hepatitis B vaccine or who has abnormal liver function tests (AII); cytomegalovirus (CMV) serology may be useful in certain persons, as discussed in 1997 USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected With the Human Immunodeficiency Virus (1) (BIII).
Considerations for Initiating Therapy in the Patient Who Has Asymptomatic
HIV Infection
It has been demonstrated that antiretroviral therapy provides clinical
benefit in HIV-infected persons who have advanced HIV disease and immunosuppression
(7 & 11). Although there is theoretical benefit to treating patients
who have CD4+T cells >500 cells/mm 3 (see Principle 3), no long-term clinical
benefit of treatment has yet been demonstrated. A major dilemma confronting
patients and practitioners is that the antiretroviral regimens currently
available that have the greatest potency in terms of viral suppression
and CD4+T cell preservation are medically complex, are associated with
several specific side effects and drug interactions, and pose a substantial
challenge for adherence. Thus, decisions regarding treatment of asymptomatic,
chronically infected persons must balance a number of competing factors
that influence risk and benefit.
The physician and the asymptomatic patient must consider multiple risks and benefits in deciding when to initiate therapy (Table 3) (see Principle 3). Several factors influence the decision to initiate early therapy: the real or potential goal of maximally suppressing viral replication; preserving immune function; prolonging health and life; decreasing the risk of drug resistance due to early suppression of viral replication with potent therapy; and decreasing drug toxicity by treating the healthier patient. Factors weighing against early treatment in the asymptomatic stable patient include the following: the potential adverse effects of the drugs on quality of life, including the inconvenience of most of the maximally suppressive regimens currently available (e.g., dietary change or large numbers of pills); the potential risk of developing drug resistance despite early initiation of therapy; the potential for limiting future treatment options due to cycling of the patient through the available drugs during early disease; the potential risk of transmission of virus resistant to protease inhibitors and other agents; the unknown durability of effect of the currently available therapies; and the unknown long-term toxicity of some drugs. Thus, the decision to begin therapy in the asymptomatic patient is complex and must be made in the setting of careful patient counseling and education. The factors that must be considered in this decision include the following: 1) the willingness of the individual to begin therapy; 2) the degree of existing immunodeficiency as determined by the CD4+T cell count; 3) the risk for disease progression as determined by the level of plasma HIV RNA (Table 4;Figure); 4) the potential benefits and risks of initiating therapy in asymptomatic persons, as discussed above; and 5) the likelihood, after counseling and education, of adherence to the prescribed treatment regimen. In regard to adherence, no patient should automatically be excluded from consideration for antiretroviral therapy simplyecause he or she exhibits a behavior or other characteristic judged by some to lend itself to noncompliance. The likelihood of patient adherence to a complex drug regimen should be discussed and determined by the individual patient and physician before therapy is initiated. To achieve the level of adherence necessary for effective therapy, providers are encouraged to utilize strategies for assessing and assisting adherence that have been developed in the context of chronic treatment for other serious diseases. Intensive patient education regarding the critical need for adherence should be provided, specific goals of therapy should be established and mutually agreed upon, and a long-term treatment plan should be developed with the patient. Intensive follow up should take place to assess adherence to treatment and to continue patient counseling to prevent transmission of HIV through sexual contact and injection of drugs.
Initiating Therapy in the Patient Who Has Asymptomatic HIV Infection
Once the patient and physician have decided to initiate antiretroviral
therapy, treatment should be aggressive, with the goal of maximal suppression
of plasma viral load to undetectable levels. Recommendations regarding
when to initiate therapy and what regimens to use are provided (Tables
5) (Tables 6). In general, any patient who has <500 CD4+T cells/mm 3 or >10,000
(bDNA) or 20,000 (RT-PCR) copies of HIV RNA/mL of plasma should be offered
therapy (AII). However, the strength of the recommendation for therapy
should be based on the readiness of the patient for treatment and a consideration
of the prognosis for risk for progression to AIDS as determined by viral
load, CD4+T cell count (Table 4; Figure), and the slope of the CD4+T cell
count decline. The values for bDNA (Table 4; Figure, first column or line)
are the uncorrected HIV RNA values obtained from the Multicenter AIDS Cohort
Study (MACS). It had previously been thought that these values, obtained
on stored heparinized plasma specimens, should be multiplied by a factor
of two to adjust for an anticipated twofold loss of RNA ascribed to the
effects of heparin and delayed processing on the stability of RNA. However,
more recent analysis suggests that the reduction ascribed to these factors
is £0.2 log, so that no significant correction factor is necessary
(Mellors J, personal communication, October 1997). RT-PCR values also are
provided (Table 4; Figure); comparison of the results obtained from the
RT-PCR and bDNA assays, using the manufacturer's controls, consistently
indicates that the HIV-1 RNA values obtained by RT-PCR are approximately
twice those obtained by the bDNA assay (12).
Thus, the MACS values must be multiplied by approximately 2 to be consistent with current RT-PCR values. A third test for HIV RNA, the nucleic acid sequence based amplification (NASBA ®), is currently used in some clinical settings. However, formulas for converting values obtained from either branched DNA (bDNA) or RT-PCR assays to NASBA ® -equivalent values cannot be derived from the limited data currently available. Currently, there are two general approaches to initiating therapy in the asymptomatic patient: a) a therapeutically more aggressive approach in which most patients would be treated early in the course of HIV infection due to the recognition that HIV disease is virtually always progressive and b) a therapeutically more cautious approach in which therapy may be delayed because the balance of the risk for clinically significant progression and other factors discussed above are considered to weigh in favor of observation and delayed therapy. The aggressive approach is heavily based on the Principles of Therapy, particularly the principle (see Principle 3) that one should begin treatment before the development of significant immunosuppression and one should treat to achieve undetectable viremia; thus, all patients who have <500 CD4+T cells/mm 3 would be started on therapy as would patients who have higher CD4+T cell numbers and plasma viral load >10,000 (bDNA) or 20,000 (RT-PCR) (Table 5). The more conservative approach to the initiation of therapy in the asymptomatic person would delay treatment of the patient who has <500 CD4+T cells/mm 3 and low levels of viremia and who has a low risk for rapid disease progression (Table 4); careful observation and monitoring would continue. Patients who have CD4+T cell counts >500/mm 3 would also be observed, except those who are at substantial risk for rapid disease progression because of a high viral load. For example, the patient who has 60,000 (RT-PCR) or 30,000 (bDNA) copies of HIV RNA/mL, regardless of CD4+T cell count, has a high probability of progressing to an AIDS-defining complication of HIV disease within 3 years (32.6% if CD4+T cells are >500/mm 3) and should clearly be encouraged to initiate antiretroviral therapy. Conversely, a patient who has 18,000 copies of HIV RNA/mL of plasma, measured by RT-PCR, and a CD4+T cell count of 410/mm 3 , has a 5.9% chance of progressing to an AIDS-defining complication of HIV infection in 3 years (Table 4). The therapeutically aggressive physician would recommend treatment for this patient to suppress the ongoing viral replication that is readily detectable; the therapeutically more conservative physician would discuss the possibility of initiation of therapy but recognize that a delay in therapy because of the balance of considerations previously discussed also is reasonable. In either case, the patient should make the final decision regarding acceptance of therapy following discussion with the healthcare provider regarding specific issues relevant to his/her own clinical situation.
When initiating therapy in the patient who has never been administered antiretroviral therapy, one should begin with a regimen that is expected to reduce viral replication to undetectable levels (AIII). Based on the weight of experience, the preferred regimen to accomplish this consists of two nucleoside reverse transcriptase inhibitors (NRTIs) and one potent protease inhibitor (PI) (Table 6). Alternative regimens have been employed; these regimens include ritonavir and saquinavir (with one or two NRTIs) or nevirapine as a substitute for the PI. Dual PI therapy with ritonavir and saquinavir (hard-gel formulation), without an NRTI, appears to be potent in suppressing viremia below detectable levels and has convenient twice-daily dosing; however, the safety of this combination has not been fully established according to FDA guidelines. Also, this regimen has not been directly compared with the proven regimens of two NRTIs and a PI; thus, the Panel recommends that at least one additional NRTI be used when the physician elects to use two PIs as initial therapy.
Substituting nevirapine for the PI, or using two NRTIs alone, does not achieve the goal of suppressing viremia to below detectable levels as consistently as does combination treatment with two NRTIs and a PI and should be used only if more potent treatment is not possible. However, some experts consider that there currently are insufficient data to choose between a three-drug regimen containing a PI and one containing nevirapine in the patient who has never been administered therapy; further studies are pending. Other regimens using two PIs or a PI and a nonnucleoside reverse transcriptase inhibitor (NNRTI) as initial therapy are currently in clinical trials with data pending. Of the two available NNRTIs, clinical trials support a preference for nevirapine over delavirdine based on results of viral load assays. Although 3TC is a potent NRTI when used in combination with another NRTI, in situations in which suppression of virus replication is not complete, restance to 3TC develops rapidly (13,14). Therefore, the optimal use for this agent is as part of a three-or-more drug combination that has a high probability of complete suppression of virus replication. Other agents in which a single genetic mutation can confer drug resistance (e.g., the NNRTIs nevirapine and delavirdine) also should be used in this manner. Use of antiretroviral agents as monotherapy is contraindicated (DI), except when no other options exist or during pregnancy to reduce perinatal transmission. When initiating antiretroviral therapy, all drugs should be started simultaneously at full dose with the following three exceptions: dose escalation regimens are recommended for ritonavir, nevirapine, and, in some cases, ritonavir plus saquinavir.
Detailed information comparing the different NRTIs, the NNRTIs, the PIs, and drug interactions between the PIs and other agents is provided (Tables 7) (Tables 12). Particular attention should be paid to drug interactions between the PIs and other agents (Tables 9) (Tables 12), as these are extensive and often require dose modification or substitution of various drugs. Toxicity assessment is an ongoing process; assessment at least twice during the first month of therapy and every 3 months thereafter is a reasonable management approach.
Initiating Therapy in Patients Who Have Advanced-Stage HIV Disease
All patients diagnosed as having advanced HIV disease, which is defined
as any condition meeting the 1993 CDC definition of AIDS (6), should be
treated with antiretroviral agents regardless of plasma viral levels (AI).
All patients who have symptomatic HIV infection without AIDS, defined as
the presence of thrush or unexplained fever, also should be treated.
Special Considerations in the Patient Who Has Advanced-Stage HIV
Disease
Some patients with OIs, wasting, dementia, or malignancy are first
diagnosed with HIV infection at this advanced stage of disease. All patients
who have advanced HIV disease should be treated with antiretroviral therapy.
When the patient is acutely ill with an OI or other complication of HIV
infection, the clinician should consider clinical issues (e.g., drug toxicity,
ability to adhere to treatment regimens, drug interactions, and laboratory
abnormalities) when determining the timing of initiation of antiretroviral
therapy. Once therapy is initiated, a maximally suppressive regimen (e.g.,
two NRTIs and a PI) should be used (Table 6). Advanced-stage patients being
maintained on an antiretroviral regimen should not have the therapy discontinued
during an acute OI or malignancy, unless concerns exist regarding drug
toxicity, intolerance, or drug interactions.
Patients who have progressed to AIDS often are treated with complicated combinations of drugs, and the clinician and patient should be alert to the potential for multiple drug interactions. Thus, the choice of which antiretroviral agents to use must be made with consideration given to potential drug interactions and overlapping drug toxicities (Tables 7) (Tables 12). For instance, the use of rifampin to treat active tuberculosis is problematic in a patient who is being administered a PI, which adversely affects the metabolism of rifampin but is frequently needed to effectively suppress viral replication in these advanced patients. Conversely, rifampin lowers the blood level of PIs, which may result in suboptimal antiretroviral therapy. Although rifampin is contraindicated or not recommended for use with all of the PIs, the clinician might consider using a reduced dose of rifabutin (Tables 8) (Tables 11); this topic is discussed in greater detail elsewhere (15). Other factors complicating advanced disease are wasting and anorexia, which may prevent patients from adhering to the dietary requirements for efficient absorption of certain protease inhibitors. Bone marrow suppression associated with ZDV and the neuropathic effects of ddC, d4T and ddI may combine with the direct effects of HIV to render the drugs intolerable. Hepatotoxicity associated with certain PIs may limit the use of these drugs, especially in patients who have underlying liver dysfunction. The absorption and half life of certain drugs may be altered by antiretroviral agents, particularly the PIs and NNRTIs whose metabolism involves the hepatic cytochrome p450 (CYP450) enzymatic pathway. Some of these PIs and NNRTIs (i.e., ritonavir, indinavir, saquinavir, nelfinavir, and delavirdine) inhibit the CYP450 pathway; others (e.g., nevirapine) induce CYP450 metabolism. CYP450 inhibitors have the potential to increase blood levels of drugs metabolized by this pathway. Adding a CYP450 inhibitor can sometimes improve the pharmacokinetic profile of selected agents (e.g., adding ritonavir therapy to the hard-gel formulation of saquinavir) as well as contribute an additive antiviral effect; however, these interactions also can result in life-threatening drug toxicity (Tables 10) (Tables 12). As a result, healthcare providers should inform their patients of the need to discuss any new drugs, including over-the-counter agents and alternative medications, that they may consider taking, and careful attention should be given to the relative risk versus benefits of specific combinations of agents.
Initiation of potent antiretroviral therapy often is associated with some degree of recovery of immune function. In this setting, patients who have advanced HIV disease and subclinical opportunistic infections (e.g., mycobacterium avium intracellulare [MAI] or CMV) may develop a new immunologic response to the pathogen, and, thus, new symptoms may develop in association with the heightened immunologic and/or inflammatory response. This should not be interpreted as a failure of antiretroviral therapy, and these newly presenting OIs should be treated appropriately while maintaining the patient on the antiretroviral regimen. Viral load measurement is helpful in clarifying this association.
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