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Changes in the DHHS ART Treatment Guidelines for Adults & and Adolescents
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Dec 1, 2007
The following changes have been made to several sections of the October 10, 2006 version of the guidelines. Additional revisions to other sections of these guidelines will be released in 2008.
Laboratory Assessment
⋅ Drug Resistance Testing - The Panel recommends performing genotypic drug resistance testing for all treatment-naive patients entering into clinical care, regardless of whether antiretroviral therapy is to be initiated
(AIII). This recommendation is based on the fact that transmitted resistance mutation may be detected at a time point more proximal to the time of infection than later. Repeat testing may be considered at the time when therapy is to be initiated (CIII).
⋅ Tropism Assay - The Panel recommends tropism testing prior to the initiation of a CCR5 antagonist, such as maraviroc (AII). Coreceptor tropism testing might also be considered for patients exhibiting virologic failure on maraviroc (or any CCR5 inhibitor) (BIII).
⋅ HLA-B*5701 Testing - The Panel recommends HLA-B*5701 testing prior to initiating abacavir therapy to reduce the risk of hypersensitivity reaction (AI). HLA-B*5701-positive patients should not be prescribed abacavir (AI), and the positive status should be recorded as an abacavir allergy in the patient's medical record (AII). When HLA-B*5701 screening is not readily available, it remains reasonable to initiate ABC with appropriate clinical counselling and monitoring for any signs of abacavir-associated hypersensitivity reaction (CIII).
When to Start Antiretroviral Therapy
1. The Panel recommends that antiretroviral therapy should be initiated in patients with history of an AIDS-defining illness or with a CD4 T-cell count <350 cells/mm3; the data supporting this recommendation are stronger for those with a CD4 T-cell count <200 cells/mm3 and with a history of AIDS (AI) than for those with CD4 T-cell counts between 200 and 350 cells/mm3 (AII).
2. The Panel also recommends treatment for the following groups regardless of CD4 T-cell count:
1. pregnant patients (AI);
2. patients with HIV associated nephropathy (AI);
3. patients coinfected with hepatitis B when treatment for hepatitis B virus is indicated (BIII).
3. The optimal time to initiate therapy in asymptomatic patients with CD4 T-cell count >350 cells/mm3 is not well defined. The decision of whether or not to start therapy in these patients should take into account the potential benefits and risks associated with therapy, comorbidities, and patient readiness and willingness to
adhere to long-term treatment.
⋅ Antiretroviral therapy may be considered in some patients with CD4 T-cell counts >350cells/mm3. (See text for further discussion.)
⋅ The necessity for patient adherence to a longterm drug regimen should be discussed in depth by the patient and clinician (AIII). Barriers to adherence should be addressed before therapy is initiated.
Management of Treatment-Experienced Patients
This section was revised to include (1) a review of the newer classes of antiretroviral agents (CCR5 antagonists and integrase inhibitors) and their roles in the management of treatment-experienced patients with virologic failure; and (2) a discussion of immunologic failure.
Tables Update
Various tables have been updated to reflect new recommendations and new information on specific antiretroviral drugs.
Selected Highlights
Use of Resistance Assays in Determining
Initial Treatment
Transmission of drug-resistant HIV strains has been well documented and has been associated with suboptimal virologic response to initial antiretroviral therapy [23-26]. The likelihood that a patient will acquire drug-resistant virus is related to the prevalence of drug resistance in persons engaging in high-risk behaviors in the community. In the United States and Europe, recent studies suggest the risk that transmitted virus will be resistant to at least one antiretroviral drug is in the range of 6%-16% [27-32], with 3%-5% of transmitted viruses exhibiting reduced
susceptibility to drugs from more than one class [23, 31]. If the decision is made to initiate therapy in a person with acute HIV infection, resistance testing at
baseline will likely optimize virologic response. Therefore, resistance testing in this situation is recommended (AIII), and a genotypic assay is generally preferred because of its more rapid turnaround time (AIII). In the absence of therapy,
resistant viruses may decline over time to less than the detection limit of standard resistance tests but may still increase the risk of treatment failure when therapy is eventually initiated. Therefore, if the decision is made to defer therapy, resistance testing during acute HIV infection should still be performed (AIII). In this situation, the genotypic resistance test result might be kept on record for several years before it becomes clinically useful. Because of the possibility of acquisition of drug-resistant virus during this period of time, repeat resistance testing at the
time ART is initiated should be considered (CIII).
Performing drug resistance testing before initiation of antiretroviral therapy in patients with chronic HIV infection is less straightforward. The rate at which
transmitted resistance-associated mutations revert to wild-type virus has not been completely delineated, but mutations present at the time of HIV transmission are more stable than those selected under drug pressure, and it is often possible to detect resistance-associated mutations in viruses that were transmitted several years earlier [33, 34]. No prospective trial has addressed whether drug resistance testing prior to initiation of therapy confers benefit in this population. However, limited data from several, but not all, studies suggest suboptimal virologic responses in persons with baseline mutations [23-26, 35-37]. In addition, a cost-effectiveness analysis of early genotypic resistance testing suggests that baseline testing in this population should be performed [38].
Therefore, resistance testing in chronically infected persons at the time of entry into HIV care is recommended (AIII). Genotypic testing is generally preferred in this situation (AIII). Repeat testing at the time ART is initiated should be considered because of the possibility that the patient may have acquired drug-resistant virus (CIII).
HLA-B*5701 SCREENING
The abacavir hypersensitivity reaction (ABC HSR) is a multiorgan clinical syndrome typically seen within the initial 6 weeks of abacavir treatment. This reaction has been reported in 5%-8% of patients participating in clinical trials when using clinical criteria for the diagnosis, and it is the major reason for early
discontinuation of abacavir. (See Table 17a.) Discontinuing abacavir usually promptly reverses HSR, whereas subsequent rechallenge can cause a rapid, severe, and even life-threatening recurrence.
Studies that evaluated demographic risk factors for ABC HSR have shown racial background as a risk factor, with white patients generally having a higher
risk (5%-8%) than black patients (2%-3%). Several groups reported a highly significant association between ABC HSR and the presence of the MHC class I allele HLA-B*5701 [49, 50]. An abacavir skin patch test (ABC SPT) was developed as a research tool to immunologically confirm ABC HSR, because
the clinical criteria used for ABC HSR are overly sensitive and may lead to false-positive ABC HSR diagnoses [51]. A positive ABC SPT is an abacavirspecific
delayed hypersensitivity reaction that results in redness and swelling at the skin site. All ABC SPT positive patients studied were also positive for the HLA-B*5701 allele [52]. The ABC SPT could be falsely negative for some patients with ABC HSR. It is not recommended as a clinical tool at this point. The PREDICT-1 study randomized patients before starting abacavir either to be prospectively screened
for HLA-B*5701 (in which HLA-B*5701-positive patients were not offered abacavir) or to standard of care (no screening, with all patients receiving abacavir) [53]. The overall HLA-B*5701 prevalence in this predominately white population was 5.6%. In this cohort, screening for HLA-B*5701 eliminated immunologic ABC HSR (defined as ABC SPT positive) compared with standard of care (0% versus 2.7%), yielding a 100% negative predictive value with respect to SPT as well as significantly decreasing the rate of clinically suspected ABC HSR (3.4% versus 7.8%). The SHAPE study corroborated the low rate of
immunologically validated ABC HSR in black patients and confirmed the utility of HLA-B*5701 screening for the risk for ABC HSR (100% sensitivity in black and white populations) [54].
On the basis of the results of these studies, the Panel recommends screening for HLA-B*5701 before starting patients on an abacavir-containing regimen (AI). HLA-B*5701-positive patients should not be prescribed abacavir (AI), and the positive status should be recorded as an abacavir allergy in the patient's medical record (AII). HLA-B*5701 testing needs to be performed only once in a patient's
lifetime, so efforts to carefully record and maintain the result and to educate the patient about its implications are important. The specificity of the HLA-B*5701 test is lower than the sensitivity (i.e., 33%-50% of HLAB* 5701 positive patients would likely not develop confirmed ABC HSR if exposed to ABC). HLAB*5701 should not be used as a substitute for clinical judgment or pharmacovigilance, because a negative HLA-B*5701 result does not absolutely rule out the possibility of some form of ABC HSR. When HLAB*5701 screening is not readily available, it remains reasonable to initiate ABC with appropriate clinical counselling and monitoring for any signs of ABC HSR (CIII).
CORECEPTOR TROPISM ASSAYS
HIV enters cells by a complex process that involves the sequential attachment to the CD4 receptor, followed by binding to either the CCR5 or CXCR4 molecules and fusion of the viral and cellular membranes [55]. The CCR5 inhibitors (i.e.,
maraviroc, vicriviroc) prevent HIV entry into target cells by binding to the CCR5 receptor [56]. Phenotypic and, to a lesser degree, genotypic assays have been developed that can determine the coreceptor tropism (CCR5, CXCR4, or both) of the patient's dominant virus population. One assay (Trofile, Monogram Biosciences, Inc., South San Francisco, CA) was used to screen patients who were participating in studies that formed the basis of approval for maraviroc, the only CCR5 inhibitor currently available. Other assays are under development and are currently used primarily for research purposes or in clinical situations in which the Trofile assay is not readily available.
Background
The vast majority of patients harbor a CCR5-utilizing virus (R5 virus) during acute/recent infection, suggesting that the R5 variant is preferentially transmitted compared with CXCR4 (X4) variants. Viruses in the majority of untreated patients
eventually exhibit a shift in coreceptor tropism from CCR5 to either CXCR4 or both CCR5 and CXCR4 (dual- or mixed-tropic; D/M-tropic). This shift is temporally associated with a more rapid decline in CD4 T-cell counts [57, 58], although whether this shift is a cause or a consequence of progressive
immunodeficiency remains undetermined [55]. Antiretroviral-treated patients with extensive drugresistance are more likely to harbor detectable X4- or D/M-tropic variants than untreated patients with comparable CD4 T-cell counts [59]. The prevalence of X4- or D/M-tropic variants increases to more than 50% in treated patients with CD4 T-cell counts less than 100 cells/mm3 [60, 61].
Phenotypic Assays
There are now at least two high-throughput phenotypic assays that can quantify the coreceptor characteristics of plasma-derived virus. Both involve the generation of laboratory viruses that express patient-derived envelope proteins (gp120 and gp41). These pseudoviruses are either replication-competent (Phenoscript assay, VIRalliance, Paris, France) or replication-defective (Trofile assay, Monogram Biosciences, Inc.) [62, 63]. These pseudoviruses can then be used to infect target cell lines that express CD4 and either CCR5 or CXCR4. In the Trofile assay, the coreceptor tropism of the patient-derived virus is confirmed by testing the susceptibility of the virus to specific CCR5 or CXCR4 inhibitors in vitro. The Trofile assay takes about 2 weeks to perform and requires a plasma viral load of at least 1,000 copies/mL. In vitro mixing experiments of R5 and X4
variants indicate that the assay can detect a minor variant with 100% sensitivity when that variant is present at a frequency of 10%, whereas the assay has
83% sensitivity when the variant is present at a frequency of 5% [62]. This sensitivity may not be sufficient to rule out the presence of clinically meaningful levels of X4- or D/M-tropic virus in patients who are initiating a CCR5 inhibitor-based regimen [64]. For unclear reasons, a minority of samples cannot be successfully phenotyped with this assay. A more sensitive assay that has improved detection of minor viral populations is under development [65].
Genotypic Assays
These assays are under investigation [66-68] but are not commercially available.
Use of Coreceptor Tropism Assays in
Clinical Practice
Coreceptor tropism assays should be used whenever the use of a CCR5 inhibitor is being considered (AII). Coreceptor tropism testing might also be considered
for patients who exhibit virologic failure on maraviroc (or any CCR5 inhibitor) (BIII).
Other potential clinical uses for the tropism assay are for prognostic purposes [57, 58, 69] or for assessment of tropism prior to starting ART, in case a CCR5
inhibitor is required later (e.g., in a regimen change for toxicity). Currently, there are not sufficient data to support these uses.
When to Start: Indications for Initiation of
Antiretroviral Therapy
The primary goals of antiretroviral therapy are to improve and/or preserve immune function and reduce HIV-associated morbidity and mortality. A potential
secondary benefit is the theoretical likelihood of reducing HIV transmission because of continued high-risk behaviors [86].
Large observational cohort studies and prognostic models provide some guidance based on the prognosis for disease-free survival as determined by baseline CD4 T-cell count (Figure A and Tables 4a, 4b) [87- 89] Potent combination antiretroviral therapy can increase and potentially normalize CD4 T-cell count in the majority of patients with maximal viral suppression regardless of baseline CD4 T-cell count [90, 91].
Currently recommended antiretroviral regimens can achieve sustained viral suppression for many years. However, immediate virologic rebound followed by
CD4 T-cell count decline is seen with most patients upon therapy interruption. Thus, once the decision is made to initiate antiretroviral therapy with currently
available drugs, treatment should be continued without interruption, except for serious toxicities or concurrent conditions that preclude oral therapy. (See
Treatment Interruption section.) Before initiating therapy, patient counselling and education should be conducted. The patient should understand the potential benefits and risks of antiretroviral therapy, including short-and long-term
adverse drug effects and the need for long-term commitment and adherence to the prescribed treatment regimen.
The Panel recommends initiation of antiretroviral therapy in patients with a history of AIDS-defining illness or with a CD4 T-cell count of <350
cells/mm3. The following sections discuss the evidence used to support this recommendation. For patients with a history of an AIDS-defining
illness or a CD4 T-cell count <200 cells/mm3, antiretroviral therapy should be initiated (AI).
HIV-infected patients with CD4 T-cell counts <200 cells/mm3 are at higher risk for development of opportunistic diseases. The role of antiretroviral
therapy is best defined in this population. Randomized controlled trials strongly support initiation of therapy in patients with CD4 T-cell count <200 cells/mm3. A prospective, controlled study provided strong evidence that treating symptomatic
patients and patients with CD4 T-cell counts <200 cells/mm3 improved survival and reduced disease progression [92].
Subsequent long-term data from multiple observational cohort studies have provided strong support for the recommendation that therapy should always be initiated before the CD4 T-cell counts decline to <200 cells/mm3 (Figure A and Table 4a) [75, 76, 88, 89, 93-95].
In the era of combination antiretroviral therapy, several large observational studies have indicated that the risk of several non-AIDS-defining conditions,
including cardiovascular diseases, liver-related events renal disease, and certain non-AIDS malignancies [97-102] is greater than the risk for AIDS in persons with
CD4 T-cell counts >200 cells/mm3; the risk for these events increases progressively as the CD4 T-cell count decreases from 350 to 200 cells/mm3.
The SMART study, a prospective, randomized, multicenter, cohort study compared treatment involving CD4 count-guided treatment interruption
(i.e., therapy was discontinued when the CD4 T-cell count exceeded 350 cells/mm3 and reinitiated when the CD4 T-cell count declined to <250 cells/mm3)
with continuous antiretroviral therapy. The risks for all-cause mortality, which was largely attributed to causes other than AIDS, and several non-AIDS defining conditions (including hepatic failure, renal disease, cardiovascular disease, and non-AIDS malignancy) were greater in participants randomized to CD4 count-guided treatment interruption than in those who received continuous therapy [103, 104].
In a subgroup analysis of the SMART study, in which treatment-naive patients with CD4 T-cell counts >350 cells/mm3 were randomized to receive immediate
antiretroviral therapy either immediately or after the CD4 T-cell count dropped to <250 cells/mm3, the risk for opportunistic diseases and serious non-AIDS events were higher in the deferred-therapy arm than in the treatment arm (absolute risk of 4.9% versus 1.0%, respectively). These data for this small subgroup suggest that delaying therapy until the CD4 T-cell count decreases to <250 cells/mm3 should be avoided [105].
Collectively, the studies cited above support the use of antiretroviral therapy in all individuals with a CD4 Tcell count <350 cells/mm3.
Antiretroviral therapy may be considered in some patients with CD4 T-cell count greater than 350 cells/mm3.
Existing data are inadequate to recommend initiation of antiretroviral therapy in all patients with CD4 T-cell counts >350 cells/mm3. Any theoretical potential
benefits could be outweighed by unknown risks or by patient-specific preferences.
The short-term risk for AIDS or death at CD4 T-cell counts 350 cells/mm3 is low (Table 4b). Thus, the potential absolute risk reductions associated with treatment in such patients are small (Table 4a). Within the ART Cohort Collaboration, the absolute 3-year risk differences between those with CD4 T-cell counts
200 to 349 cells/mm3 and those with CD4 T-cell counts 350 cells/mm3 were only 1.3% (for those with HIV-RNA < 100,000 copies/mL) and 1.7% (for those
with HIV-RNA 100,000 copies/mL) [88]. These differences were similar through 5 years of observation [96]. The cost-effectiveness of early initiation of antiretroviral therapy in these patients is unknown.
Data from the AIDS Therapy Evaluation Project, Netherlands (ATHENA), have demonstrated that patients who started therapy at CD4 T-cell counts >350 cells/mm3 were significantly more likely to achieve CD4 T-cell counts >800 cells/mm3 after 7 years of therapy than those who initiated therapy at lower CD4 T-cell counts [91]. A long-term study based on the Johns Hopkins Clinical Cohort
demonstrated that patients who initiated ART with a CD4 T-cell count <350 cells/mm3 were significantly less likely to achieve a CD4 T-cell count >500
cells/mm3 after 6 years of HAART compared with those who started therapy at CD4 T-cell counts >350 cells/mm3 [109].
Earlier treatment of HIV infection may also have positive public health implications, as it may reduce HIV transmission [86]. This may have significant
implication in individuals in discordant relationships (i.e., HIV-infected individuals with HIV-negative sexual partners) or in individuals who continue to engage in risky behaviors.
Despite possible benefits of treatment of persons with CD4 T-cell counts >350 cells/mm3, there are also considerations that argue against therapy. First, the
potential absolute reduction in risk of non-AIDS events/morbidity resulting from antiretroviral responses in CD4 T-cell count increase and viral load suppression is not large. Second, although there are now several reasonably safe and well-tolerated options for first-line regimens, the long-term toxicities remain unknown. Third, antiretroviral treatment requires lifelong adherence to therapy. Some patients may find that the need to take daily medications decreases quality of life, even without side effects. Lastly, nonadherence to the regimen may promote the
development of drug resistance.
The level of HIV RNA in a patient with a higher CD4 T-cell count is not strongly associated with short-term risk of AIDS/death and is a less important criterion for
initiation of therapy than the CD4 T-cell count. Nevertheless, a high viral load is a predictor of more rapid progression to AIDS overall. Some experts may take viral load into consideration when deciding whether or not to start therapy in patients with CD4 Tcell counts >350 cells/mm3 [87, 110].
Clinical scenarios, the presence of comorbidities, age, patient readiness, potential impact on quality of life, and adherence should be considered in the decision of when and if to initiate therapy in patients with a CD4 T-cell count >350 cells/mm3. Some experts suggest that antiretroviral therapy should be initiated in the subset of persons who have evidence of a rapid decline in CD4 T-cells (e.g., a decrease of >120 cells/mm3 per annum) before it drops to a CD4 T-cell count of 350 cells/mm3 in order to avoid rapid immunologic deterioration and subsequent clinical progression.
Nelfinavir in pregnant women (EIII).
In September 2007, the FDA and the manufacturer of nelfinavir issued a warning regarding the presence of small amounts of a byproduct (ethyl methanesulfonate or EMS), during the manufacturer process, in the final product of nelfinavir. EMS is an animal carcinogen, mutagen, and teratogen. Because of the unknown risk
of EMS to unborn fetus, nelfinavir should not be used in pregnant women or in women anticipating conception until further notice. Women who become pregnant while on nelfinavir should switch to an alternative antiretroviral agent.
Management of the Treatment - Experienced Patient
A persistently low CD4 T-cell count while on suppressive antiretroviral therapy is associated with a small, but appreciable, risk of AIDS- and non-AIDS-related morbidity and mortality [259, 260]. For example, in the FIRST study [261] , a low CD4 T-cell count on therapy was associated with an increased risk for AIDS-related complications (adjusted hazard ratio of 0.57 for CD4 T-cell count
100 cells/mm3 higher). Similarly, a low CD4 T-cell count was associated with an increased risk for non- AIDS events, including cardiovascular, hepatic, renal and cancer events. Other studies support these associations [97, 102, 103].
Adding at least two, and preferably three, fully active agents to an optimized background antiretroviral regimen can provide significant antiretroviral activity (BII).
⋅ Immunologic failure can be defined as a failure to achieve and maintain an adequate CD4 response despite virologic suppression.
⋅ For immunologic failure, current medications, untreated coinfection, and serious medical conditions should be assessed.
⋅ There is no consensus for when and how to treat immunologic failure.
Ideally, one should design a regimen with at least two, and preferably three, fully
active drugs on the basis of drug history, resistance testing, or new mechanistic class (BII) [41, 230-237].
Tipranavir and darunavir are the two newest protease inhibitors approved for patients who are highly treatment-experienced or have HIV-1 strains
resistant to multiple PIs based on demonstrated activity against PI-resistant viruses [238, 239]. However, with ongoing viremia and the accumulation of additional mutations, antiretroviral activity is time-limited unless the regimen contains other active drugs (e.g., enfuvirtide, a CCR5 inhibitor, or an integrase inhibitor).
Newer Agents
Maraviroc, the first approved CCR5 inhibitor, is an antiretroviral drug that specifically binds to the CCR5 receptor of the CD4 T-cell, thereby inhibiting HIV
strains that use this coreceptor for cellular entry. Phase III clinical studies enrolled triple-class, treatment-experienced patients who experienced failure on their current antiretroviral regimens with detectable viremia with only CCR5-tropic (R5) viral strains (documented using a tropism assay). In these studies, maraviroc resulted in significantly better virologic responses over 24 weeks compared with placebo when added to an antiretroviral regimen that was optimized based on treatment history and drug resistance testing [234,
235]. In another study, maraviroc did not demonstrate significant virologic activity in treatment-experienced patients with viremia with only X4 virus, a dual/mixed
population of X4 and R5 viruses, or an indeterminate tropism result, although CD4 increases were seen [245]. Maraviroc was generally safe and well
tolerated, although theoretical concerns about the longer-term safety of CCR5 inhibitors require additional assessment. With a unique mechanism of action and documented short-term efficacy and safety, maraviroc should be considered a fully active antiretroviral agent in treatment-experienced patients who have only R5 virus and who are naive to CCR5 inhibitors.
Raltegravir, the first approved HIV integrase inhibitor, specifically inhibits the final step in integration, strand transfer of viral DNA to host cell DNA. Phase III
clinical studies enrolled, triple-class, treatment-experienced patients who experienced failure on their current antiretroviral regimens with detectable
viremia. In these studies, raltegravir resulted in significantly better virologic responses over 24 weeks compared with placebo when added to an
antiretroviral regimen that was optimized based on treatment history and drug resistance testing [236, 237]. Raltegravir was generally safe and well
tolerated. With a unique mechanism of action and documented short-term efficacy and safety, raltegravir should be considered a fully active antiretroviral agent in treatment-experienced patients who are naive to HIV integrase inhibitors.
Etravirine, an NNRTI, has activity in vitro against viral strains with mutations that confer resistance to efavirenz and nevirapine [246]. Phase III studies enrolled triple-class, treatment-experienced patients who had at least one NNRTI-associated drug resistance mutation and who were experiencing failure
on their current antiretroviral regimen with detectable viremia. In these studies, etravirine resulted in significantly better virologic responses over 24 weeks
compared with placebo when added to an optimized background antiretroviral regimen that included darunavir/ritonavir [247, 248]. Etravirine was generally safe and well tolerated. With activity against some NNRTI-resistant viral strains, etravirine may provide significant virologic activity in treatment-experienced
patients, depending on the amount of NNRTI-resistance. (See Table 27 for information regarding etravirine expanded access program.)
Other investigational drugs with newer mechanisms of action demonstrate short-term antiretroviral activity in patients with resistance to reverse transcriptase
inhibitors and protease inhibitors [249-251] and are also under investigation in clinical trials.
CCR5 Antagonist Drug Interaction
Maraviroc, the first FDA-approved CCR5 antagonist, is a substrate of CYP3A enzymes. As a consequence, the concentrations of maraviroc can be significantly increased in the presence of strong CYP3A inhibitors (such as ritonavir and other PIs, except for ritonavir-boosted tipranavir) and are reduced when used with CYP3A inducers, such as efavirenz or rifamin. Dose adjustment is necessary when used in combination with these agents. (See Table 14a for dosage recommendations) Maraviroc is neither an inducer nor an inhibitor of CYP3A system. It does not alter the pharmacokinetic of the drugs evaluated in interaction studies to date.
Integrase Inhibitor Drug Interaction
Raltegravir, an HIV integrase strand transfer inhibitor, is primarily eliminated by glucuronidation mediated by the enzyme UDP-glucuronosyl-transferases (UGT1A1). Strong inducers of UGT1A1 enzymes (such as rifampin) can significantly reduce the concentration of raltegravir. The significance of this interaction is unknown; thus this combination should be used with caution or an alternative therapy should be considered. Other inducers of UGT1A1, such as
efavirenz, tipranavir/ritonavir, or rifabutin, can also reduce raltegravir concentration. A pharmacokinetic interaction should be considered if optimal virologic response is not achieved when these drugs are used in
combination.
HBV/HIV Coinfection
Entecavir has activity against HIV, and its use in patients with dual infection has been associated with selection of the M184V mutation that confers resistance to lamivudine and emtricitabine [327, 328]. Therefore, entecavir should be used only with a fully suppressive antiretroviral regimen in HIV/HBV coinfected patients. NRTI backbone of an antiretroviral regimen, which will result in treatment of both infections. Because the preferred antiretroviral regimens all contain either lamivudine or emtricitabine, it is not possible to treat only HIV infection without using a nonpreferred regimen. To avoid development of
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