| |
Updated Change in DHHS HIV Treatment Guidelines as of October 10, 2006: Reyataz/r & FosAPV/r added to Preferred Regimens for Naives
|
| |
| |
Several key changes have occurred to the Dept of HHS HIV Treatment Guidelines.
Boosted Reyataz and boosted Fosamprenavir added to 'Preferred' Firstline Regimens. Unboosted Reyataz has been added as an 'Alternative' Regimen. Viracept (nelfinavir) and RTV-boosted Invirase are now listed as 'possible' regimen options.
Preferred Firstline PI/NNRTI regimens are:
Kaletra twice daily
Atazanavir/RTV
Fosamprenavir/RTV twice daily
Preferred NRTI regimens are:
Tenofovir+FTC (co-formulated)
AZT/3TC (co-formulated)
ALTERNATIVE REGIMENS are:
Unboosted Reyataz
Unboosted fosamprenavir
Fosamprenavir/RTV once daily
Kaletra once daily
Abacavir/3TC (co-formulated)
ddI/3TC
The Panel revised its recommendations for preferred and alternative antiretroviral components based on reported results from several randomized trials in treatment-naive patients and on safety data that have emerged since the last revision. Specific recommendations can be found in Tables 6a and 6b. Rationale for the recommendations is outlined in the text.
The revised recommendations for antiretroviral-naive patients are summarized below. Clinicians are recommended to construct a regimen by choosing one component from Column A + one component from Column B.
The Panel considers atazanavir + ritonavir (AIII), fosamprenavir + ritonavir (given twice daily, AII), and lopinavir/ritonavir (co-formulated, given twice daily, AII) as preferred PIs for the treatment-naive patient.
The recommendation is based on clinical trial data for virologic potency, the barrier for virologic resistance, convenience, and tolerability. Alternative PIs include atazanavir (BII), fosamprenavir (BII), once-daily fosamprenavir + ritonavir (BII), or once-daily lopinavir/ritonavir (BII).
Data Used for Making Recommendations. In its deliberations for the guidelines, the Panel reviews clinical trial data published in peer-reviewed journals and data prepared by manufacturers for FDA review. In selected cases, data presented in abstract format in major scientific meetings are also reviewed. The first criteria for selection are data from a randomized, prospective clinical trial with an adequate sample size, demonstrating potency as measured by durable viral suppression and immunologic enhancement (as evidenced by increased CD4+ T cell count). Few of these trials include clinical endpoints, such as development of AIDS-defining illness or death. Thus, assessment of regimen efficacy and potency are mostly based on surrogate marker endpoints. A summary of selected prospective comparative trials for initial therapy with at least 48-week data can be seen in Table 10.
The Panel reviewed data across numerous clinical trials in arriving at preferred versus alternative ratings in Table 6a and the other possible options in Table
6b. Components are designated as preferred for use in treatment-naive patients when clinical trial data have demonstrated optimal efficacy and durability with
acceptable tolerability and ease of use. Alternative components refer to those for which clinical trial data show efficacy but also show disadvantages compared
with preferred components in terms of antiviral activity, durability, tolerability, or ease of use. In some cases, based on individual patient characteristics and needs, a regimen listed as an alternative regimen may actually be the preferred regimen in that patient. Other possible options are components that have inferior
virologic efficacy or greater or more serious toxicities than the preferred and alternative regimens. With improved choices of more effective and more
convenient regimens, some of the agents or combinations previously recommended by the Panel as alternative regimens have been removed from the
list or placed as other possible options.
Preferred PI Components (in alphabetical order).
Ritonavir-boosted Atazanavir (AIII). Atazanavir is an azapeptide PI with the advantages of once-daily dosing. Ritonavir-boosting of atazanavir enhances the
concentrations of atazanavir and demonstrates similar efficacy as unboosted atazanavir in combination with two NRTIs in treatment-naive patients [103]. The
comparative virologic efficacy to unboosted atazanavir in treatment-naive patients, the improved pharmacokinetics with ritonavir-boosting, and the experience of atazanavir + ritonavir in treatmentexperienced patients [104] supports its designation as a preferred regimen. The main adverse effect
associated with atazanavir + ritonavir use is indirect hyperbilirubinemia, with or without jaundice or scleral icterus, but without concomitant hepatic transaminase
elevations. The lipid effects associated with atazanavir + ritonavir are uncertain. Patients who receive concomitant therapy with tenofovir or efavirenz should use ritonavir-boosted ataznavir to overcome the pharmacokinetic interactions between unboosted atazanavir and these two agents. Atazanavir + ritonavir requires acidic gastric pH for dissolution. Thus, concomitant use of drugs which raise gastric pH, such as antacids, H2 antagonists, and particularly proton pump inhibitors, may significantly impair absorption of atazanavir + ritonavir.
Ritonavir-boosted Fosamprenavir (twice daily) (AII). Fosamprenavir is a prodrug of the protease inhibitor amprenavir. A head-to-head, randomized trial compared twice-daily ritonavir-boosted fosamprenavir with lopinavir/ritonavir, each in combination with abacavir and lamivudine in antiretroviral-naive patients. At week 48, 73% of the patients in the ritonavir-boosted fosamprenavir arm and 71% of those in the lopinavir/ritonavir arm achieved viral loads of <400 copies/mL (95% CI around treatment difference: -4.84 to 7.05). Clinical and laboratory adverse events did not differ between the regimens. In this study of treatment-naive subjects, twice-daily ritonavir-boosted fosamprenavir was non-inferior to twice-daily lopinavir/ritonavir, and this supports the recommendation of twice-daily ritonavir-boosted fosamprenavir as a preferred PI component [105].
Lopinavir/ritonavir (co-formulated; twice daily) (AII). In several clinical trials, regimens containing twice-daily lopinavir/ritonavir with two NRTIs have shown potent virologic activity in treatment-naive patients. In a randomized, placebo-controlled trial comparing lopinavir/ritonavir with nelfinavir (each with stavudine and lamivudine) in 653 patients, lopinavir/ritonavir was superior to nelfinavir in
maintaining a viral load <400 copies/mL through 48 weeks (84% versus 66% with persistent virologic response through 48 weeks; hazard ratio = 2.0; 95% CI: 1.5 to 2.7) [106]. Overall adverse event rates and study discontinuation rates because of adverse events were similar in the two groups. No evidence of
genotypic or phenotypic resistance to PIs was detected in the 51 lopinavir/ritonavir-treated patients with >400 copies/mL at up to 48 weeks follow-up. In contrast, D30N and/or L90M mutations were detected in 43 of 96 (45%) of nelfinavir-treated patients [107]. A 7-year follow-up study of lopinavir/ritonavir and two NRTIs showed sustained virologic suppression in patients who were maintained on the originally assigned regimen [108]. The major adverse effects of lopinavir/ritonavir are gastrointestinal intolerance (particularly diarrhea) and hyperlipidemia, especially hypertriglyceridemia, necessitating pharmacologic
management in some patients. The tablet formulation reduces the pill count to two pills twice daily, allows administration without food restriction, and eliminates
the need for refrigeration.
In a pharmacokinetic study of standard dosing using capsule formulation, lopinavir plasma concentrations were significantly reduced during the third trimester of pregnancy [109]. The implication of this pharmacokinetic change on virologic outcome in the mother and the risk of perinatal HIV transmission
remain unknown. Further studies are underway to examine the pharmacologic and clinical efficacy of increased dosing of lopinavir/ritonavir in this population and with the new tablet formulation.
Alternative PI-based regimens (in alphabetical order)
Atazanavir (BII). Unboosted atazanavir is given once daily and has fewer adverse effects on lipid profiles than other available PIs. Three studies compared atazanavir-based combination regimens to either nelfinavir- or efavirenz-based regimens. These studies established similar virologic efficacy among atazanavir 400mg once daily and both comparator treatment groups in antiretroviral-naive patients after 48 weeks of therapy [93, 110, 111]. Atazanavir may be chosen as initial therapy for patients when a once-daily regimen (without ritonavir) is desired and in patients with underlying risk factors when hyperlipidemia may be particularly undesirable. Patients who receive concomitant therapy with tenofovir or efavirenz should use ritonavir-boosted atazanavir to overcome the adverse pharmacokinetic interactions between unboosted atazanavir and these two agents. Atazanavir requires acidic gastric pH for dissolution. Thus, concomitant use of drugs which raise gastric pH, such as antacids, H2 antagonists, and proton pump inhibitors, may significantly impair its absorption.
Fosamprenavir (BII) and Ritonavir-Boosted Fosamprenavir (once daily) (BII). Fosamprenavir can be given without ritonavir (twice daily) or as a once-daily ritonavir-boosted regimen. Two studies compared twice-daily fosamprenavir and once-daily ritonavir-boosted fosamprenavir to nelfinavir [112, 113]. In the first trial, more patients randomized to fosamprenavir achieved viral suppression at 48 weeks than those assigned to nelfinavir, with greater differences seen in those patients with pretreatment viral load >100,000 copies/mL [112]. Once-daily ritonavir-boosted fosamprenavir had similar virologic activity to nelfinavir in the second trial [113].
Lopinavir/ritonavir (once daily) (BII) Lopinavir/ritonavir can be given once daily in treatment-naive patients. When compared with the traditional twice-daily dosing, giving the same total dose once daily results in a similar mean area under the concentration-time curve but a lower mean trough concentration. In a randomized trial comparing oncedaily and twice-daily lopinavir/ritonavir in
combination with tenofovir and emtricitabine, a similar proportion of patients achieved viral suppression to <50 copies/mL at 48 weeks [114]. However, a greater incidence of moderate to severe diarrhea was reported in the patients randomized to the once-daily arm (16% vs. 5%). A lower trough concentration is expected with the once-daily dosing, so this dosing strategy is not recommended in PI-experienced patients, especially in those who may have HIV-1 strains with reduced susceptibility to lopinavir.
Other PI Options - Inferior to Preferred or
Alternative PI Components
Nelfinavir (CII). Nelfinavir is generally well tolerated except for diarrhea, which occurs in up to 30%-40% of patients. Clinical trials have shown a virologic effect of nelfinavir similar to atazanavir [110] and to once-daily ritonavir-boosted fosamprenavir [115] but inferior to twice-daily lopinavir/ritonavir [106], unboosted fosamprenavir [112], and efavirenz [88] in terms of virologic suppression at 48 weeks. In contrast to other PIs (particularly ritonavir-boosted PIs), genotypic resistance is often seen in patients with virologic rebound on nelfinavir [107, 116]. Most commonly a D30N mutation is selected, although the presence of the D30N mutation alone does not confer resistance to other PIs. A smaller percentage of patients may select the multiple-PI-resistant L90M mutation upon virologic rebound, which may limit the choice of PIs as future options [107, 116]. Because of suboptimal virologic responses and more drug resistance following virologic failure compared with other regimens, nelfinavir is recommended only when preferred or alternative regimens cannot or should not be used. Among the currently marketed PIs, nelfinavir has the most safety and pharmacokinetic data in pregnant women. The approved dosage of 1,250mg twice daily produces similar pharmacokinetic profiles during the third trimester of pregnancy as compared with non-pregnant state [117]. Thus no dosage adjustment is deemed necessary when nelfinavir is used during pregnancy.
Ritonavir-boosted Saquinavir (CII). The low oral bioavailability of saquinavir hard-gel capsules makes this drug suboptimal when used as the only PI. Ritonavir inhibits CYP 3A4 isoenzymes in both the intestine and the liver. The addition of low-dose ritonavir to saquinavir results in a significant increase in oral bioavailability and a delay in saquinavir clearance. This leads to a higher peak saquinavir concentration, a longer elimination half-life, and a higher pre-dose concentration. In a comparative study in which a substantial number of patients were PInaive, low-dose (100mg twice daily) ritonavir-boosted saquinavir (1,000mg twice daily) had a similar virologic response but better tolerability than the ritonavir + indinavir combination [101]. However, a similarly designed study demonstrated decreased virologic responses with ritonavir-boosted saquinavir
compared with lopinavir/ritonavir [102].
Eight nucleoside/nucleotide HIV-1 reverse transcriptase inhibitors (NRTIs) are currently approved in the U.S. Dual-NRTI combinations are commonly utilized components of combination antiretroviral regimens upon which the addition of an
NNRTI or a PI (often boosted with ritonavir) confers potency for long-term efficacy.
Most dual-NRTI combinations used in clinical practice consist of a primary NRTI in combination with lamivudine or emtricitabine. Both lamivudine and emtricitabine have negligible side effects, and each selects for the M184V mutation that can confer improved susceptibility to zidovudine or tenofovir
[118].
All NRTIs except for didanosine can be taken without food restriction. Adherence may be further improved with once-daily dosing (currently possible with abacavir, didanosine, emtricitabine, lamivudine, and tenofovir) and with fixed-dosage combination products, such as abacavir/lamivudine, tenofovir/emtricitabine (with or without efavirenz), or zidovudine/lamivudine.
The Panel's recommendations on specific dual-NRTI options are made on the basis of virologic potency and durability, short- and long-term toxicities, the
propensity to select for resistance mutations, dosing convenience, and drug-drug interaction potential. The following sections list the Panel-recommended dual-NRTI combinations and discuss the rationale behind each recommendation.
Preferred Dual-NRTI Components:
Tenofovir/emtricitabine (co-formulated) (AII). Tenofovir is a nucleotide analog with potent activity against HIV and hepatitis B virus and with a long intracellular half-life that allows for once-daily dosing. The fixed-dose combinations of tenofovir/emtricitabine and tenofovir/emtricitabine/efavirenz are both administered as one pill once daily and are designed to improve adherence.
Tenofovir, when used with either lamivudine or emtricitabine as part of an efavirenz-based regimen in treatment-naive patients, demonstrated potent virologic suppression through 144 weeks [85] and was not inferior to zidovudine/lamivudine in virologic efficacy at 48 and 96 weeks [119, 120]. In the Gilead 934 study, more subjects in the zidovudine/lamivudine arm developed lower limb fat on DEXA scans and anemia at 96 weeks compared with the
tenofovir/emtricitabine arm [119]. A tenofovir-based dual-NRTI combination has not been compared head-to- head with another dual-NRTI combination in a PI-based regimen. In a study comparing once- and twice-daily lopinavir/ritonavir, using tenofovir/emtricitabine as the dual-NRTI backbone, the 48-week virologic
efficacy was similar to other trials in treatment-naive subjects [114].
Renal impairment, manifested by increases in serum creatinine, glycosuria, hypophosphatemia, and acute tubular necrosis, has been reported with tenofovir use [121, 122]. The extent of this toxicity is still undefined. Renal function, urinalysis, and electrolytes should be monitored in patients while on tenofovir. In
patients with some degree of pre-existing renal insufficiency, tenofovir dosage adjustment is required; however, no safety data using the dosage adjustment guidelines for renal dysfunction are available.
Zidovudine/lamivudine (co-formulated) (AII). The dual-NRTI combination of zidovudine/lamivudine has been the main dual-NRTI component in multiple clinical trials examining the potency of various NNRTI- and PI-based regimens [86, 88, 89, 93, 123 125]. This combination has extensive experience in durability, safety, and tolerability. A fixed-dose combination of zidovudine/lamivudine is available for one-tablet, twice-daily dosing. Bone marrow suppression, manifested by macrocytic anemia and/or neutropenia, may be seen in some patients. Selection of the lamivudine-associated M184V mutation has been associated with increased susceptibility to zidovudine or tenofovir.
Alternative Dual-NRTI Components:
Abacavir/lamivudine (co-formulated) (BII). In a comparative trial of abacavir/lamivudine and zidovudine/lamivudine (both given twice daily and
combined with efavirenz), subjects from both arms achieved similar virologic responses. The abacavir-treated subjects experienced a greater CD4+ T cell
increase at 48 weeks (+209/mm3 in the abacavir arm vs. +155/mm3 in the zidovudine arm, p=0.005) [126]. However, the potential for serious abacavir-associated hypersensitivity reactions in 5%-8% of patients warrants
placement of abacavir/lamivudine as an alternative dual-NRTI option at this time. The fixed-dose combination of abacavir/lamivudine allows for one-pill, once-daily dosing.
Didanosine + (emtricitabine or lamivudine) (BII). To date, the clinical trial experience with didanosine + emtricitabine or lamivudine is limited. The FTC-301A trial tested didanosine + emtricitabine with efavirenz and demonstrated potent virologic suppression (78% <50 copies/mL at 48 weeks) [30]. In a small, single-arm study of didanosine + lamivudine + efavirenz as once-daily
therapy, 77% of the patients achieved HIV RNA <50 copies/mL at 48 weeks [127]. Because of the limited data, didanosine together with either emtricitabine or lamivudine can only be recommended as an alternative dual-NRTI component.
Acceptable Alternative Dual-NRTI Option but
Inferior to Preferred or Alternative Components.
Stavudine + Lamivudine (CII) Despite durable virologic efficacy in some studies [85, 128], long-term use of stavudine has been associated with irreversible and sometimes serious toxicities, such as peripheral neuropathy, lipoatrophy, and serious and lifethreatening lactic acidosis with hepatic steatosis with
or without pancreatitis, and rapidly progressive neuromuscular weakness [129-131]. Because there are a number of less toxic NRTI options at this time, the
Panel recommends a dual-NRTI component consisting of stavudine + lamivudine (or emtricitabine) only when the preferred or alternative dual-NRTI options listed above cannot be used.
NRTIs and Hepatitis B.
Three of the current NRTIs, emtricitabine, lamivudine, and tenofovir, all have activity against hepatitis B virus. Lamivudine is currently approved as a treatment for hepatitis B infection. It is important to note that patients with hepatitis B and HIV coinfection may be at risk of acute exacerbation of hepatitis after initiation or upon discontinuation of these drugs [132-134]. Thus, these patients should be monitored closely for clinical or chemical hepatitis if these drugs are to be initiated or discontinued.
Triple-NRTI Regimens
A triple-NRTI combination regimen has multiple advantages: fewer drug-drug interactions, low pill burden, availability of a fixed-dose combination (zidovudine/lamivudine/abacavir combined as Trizivir), and the ability to spare patients from potential side effects seen with PIs and NNRTIs. However, several clinical trials that studied triple-NRTI regimens have shown suboptimal virologic
activity [89, 90, 135-139]. The Panel recommends that a triple-NRTI regimen
consisting of abacavir/lamivudine/zidovudine should only be used when a preferred or an alternative NNRTI-based or a PI-based regimen may be less
desirable because of concerns over toxicities, drug interactions, or regimen complexity (CII).
Abacavir/lamivudine/zidovudine (co-formulated) (CII).
Abacavir/lamivudine/zidovudine is the only triple-NRTI combination for which randomized, controlled trials are available. Abacavir/lamivudine/zidovudine demonstrated comparable antiretroviral activity to indinavir [123, 124] and nelfinavir [140] but was inferior virologically to an efavirenz-based regimen [89].
Zidovudine/lamivudine + tenofovir (DII): The DART study demonstrated virologic responses in patients taking zidovudine/lamivudine + tenofovir [141]; however, comparative data with standard regimens are not available.
|
|
| |
| |
|
|
|
