OR WAIT null SECS
The challenge of controlling HIV in patients with resistance to antiretrovirals has contributed to accelerated research into treatments with novel antiretroviral activity.
Research into the treatment of HIV infection has resulted in the development of 5 antiretroviral (ARV) drug classes: entry inhibitors, including fusion inhibitors and chemokine coreceptor (CCR) inhibitors; nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs); non-nucleoside reverse transcriptase inhibitors (NNRTIs); integrase inhibitors; and protease inhibitors (PIs). With the approval of the first PIs, the treatment of HIV shifted to highly active ARV therapy (HAART). HAART, which refers to a combination of agents from ≥2 different ARV classes, is a standard approach for treating HIV infection today. The challenge of controlling HIV in patients with resistance to ARVs has contributed to accelerated research into treatments with novel ARV activity. This research has led to the introduction of a CCR5 inhibitor, an integrase inhibitor, and a new NNRTI. This article provides a review of recently approved and investigational agents for the treatment of HIV-1 infection in adult patients, as well as an overview of ARV treatment guidelines. (Formulary. 2009;44:47–54.)
ARV TARGETS IN THE HIV LIFE CYCLE
Packaged within the HIV capsid, the virus carries the infectious single-stranded HIV RNA and the enzymes needed for development of a mature virion, including reverse transcriptase, protease, and integrase. Surrounding the HIV virus are glycoprotein 120 (gp120) receptors that are anchored to the viral envelope by glycoprotein 41 (gp41) molecules. These gp 120 receptors have a high affinity for CD4 receptors found on cells such as CD4+ T lymphocyte cells, macrophages, and dendritic cells.4
HIV gp 120 attaches to human host CD4 receptors, which allows binding to chemokine coreceptors on CD4 cells, specifically chemokine coreceptor 5 (CCR5) (expressed on dendritic cells, macrophages, and T lymphocyte cells) or CXC chemokine coreceptor 4 (CXCR4) (expressed only on T lymphocyte cells). This binding reveals gp 41, thus allowing fusion of the viral envelope to the plasma membrane on CD4+ T lymphocyte cells and release of the HIV capsid contents into the cell's cytoplasm. Entry inhibitors target this early step in the HIV life cycle.5,6 The 2 subclasses of entry inhibitors currently marketed in the United States include fusion inhibitors (FIs) and CCR5 coreceptor antagonists (ie, CCR5 inhibitors).
Once the HIV RNA is released into the CD4 cell's cytoplasm, reverse transcriptase transcribes the single-stranded RNA into a double-stranded complementary viral DNA, which then migrates to the nucleus and is integrated into the cell genome via integrase. One of the treatment targets in this stage of the HIV life cycle includes inhibition of reverse transcriptase in the cytoplasm of the cell; 2 classes of drugs, known as nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), target this enzyme. NRTIs are competitive inhibitors of reverse transcriptase and require intracellular phosphorylation, whereas NNRTIs are noncompetitive inhibitors of the same enzyme and do not require intracellular phosphorylation. Another target for ARV therapy includes inhibition of the enzyme integrase.7
After HIV DNA is integrated into the host cell and HIV replication is induced, the CD4+ T lymphocyte cells produce strands of viral Gag (p55) and Gag-Pol (p160) polyproteins. The viral enzyme protease cleaves these strands to create individual HIV proteins and enzymes, which then assemble to produce new HIV virions. Once these virions mature, they are capable of infecting healthy human host cells. Protease inhibitors (PIs) interfere with the strand cleavage/assembly step of the HIV life cycle.8 HIV maturation inhibitors are in the early stages of clinical research.
RECENTLY APPROVED AND SELECTED INVESTIGATIONAL ARVS
With the emergence of resistant strains of HIV, the need for salvage therapy with novel ARV activity is apparent. Three ARVs that target various stages of the HIV life cycle have recently been approved by FDA (the entry inhibitor maraviroc, the integrase inhibitor raltegravir, and the NNRTI etravirine).
Entry inhibitors. Maraviroc is a CCR5 inhibitor that was approved by FDA in August 2007. Before initiation of therapy with maraviroc, an HIV tropism assay is necessary to determine which chemokine coreceptor the patient's strain of HIV uses for attaching to and entering host cells. Maraviroc is indicated only for treatment-experienced patients with HIV strains that use the CCR5 coreceptor exclusively; however, recent studies have also evaluated its use as a first-line therapy.9 It has been proposed that CCR5 inhibitors may be most useful in acute and early infection given the predominance of CCR5 coreceptors in early disease, but large-scale studies are needed to test this theory further.10
FDA approval of maraviroc was based on results from two phase 3 placebo-controlled studies, the Efficacy and Safety of Maraviroc plus Optimized Background Therapy In Viremic, Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and 2 trials, which demonstrated that treatment with maraviroc leads to superior viral control compared with optimized background therapy (OBT) alone. The pooled 48-week analysis of these trials demonstrated that 239 of 426 patients (56%) treated with maraviroc had HIV-1 RNA <400 copies/mL compared with 47 of 209 patients (22%) who received OBT alone. At 48 weeks, 194 of 426 patients (46%) treated with maraviroc had HIV-1 RNA <50 copies/mL versus 35 of 209 patients (17%) in the OBT arm. The mean change in plasma HIV-1 RNA at Week 48 was –1.84 log10 copies/mL in the maraviroc arm versus –0.78 log10 copies/mL in the OBT arm. The mean increase in CD4+ T lymphocyte counts was 124 cells/mm³ in the maraviroc arm versus 60 cells/mm³ in the OBT arm.11
The most common adverse events observed with maraviroc at a higher frequency than that observed with OBT (>8% incidence) included upper respiratory tract infections, cough, pyrexia, rash, and dizziness. During phase 3 studies, an increased risk of cardiovascular events (eg, myocardial ischemia and/or infarction) was noted in the maraviroc treatment arm compared with the OBT arm (1.3% vs 0). A boxed warning regarding hepatotoxicity that may be preceded by systemic allergic reaction is included in the prescribing information for maraviroc.
Vicriviroc is another CCR5 inhibitor under development by Schering-Plough. Phase 3 trials in treatment-experienced patients are currently under way.12
Less advanced in clinical development are various CXCR4 inhibitors, several of which have failed in development because of hepatotoxicity. The latest CXCR4 inhibitor, AMD070 (Genzyme), is currently in phase 1/2 studies. The most common adverse reactions observed in a dose-escalating study included sinus tachycardia, transient headaches, and gastrointestinal (GI) symptoms.13
Integrase inhibitors. Integrase inhibitors work by blocking HIV integrase from incorporating viral DNA into the human host cell's genome. The integrase inhibitor raltegravir received accelerated FDA approval in October 2007. Raltegravir is currently approved for the treatment of HIV in treatment-experienced patients; however, some studies in treatment-naïve patients have also been conducted, and others are in progress.14,15
FDA approval of raltegravir was based on the results of Blocking Integrase in Treatment Experienced Patients With a Novel Compound Against HIV, Merck (BENCHMRK) 1 and 2, the phase 3 trials conducted in treatment-experienced patients. In combined data from both studies after 16 to 24 weeks, 77.5% of patients treated with raltegravir 400 mg twice daily had HIV viral load levels <400 copies/mL compared with 41.9% to 43% of patients in the placebo arm (P<.001). A total of 61.8% (Wk 16) to 62.1% (Wk 48) of patients in the raltegravir arm achieved HIV viral loads <50 copies/mL compared with 34.7% (Wk 16) to 32.9% (Wk 48) of patients in the OBT arm (P<.001). Increases in CD4+ T lymphocyte counts were also notable in patients who received raltegravir, with a mean increase of 109 cells/mm3 in raltegravir-treated patients versus 45 cells/mm3 among placebo-treated patients in the combined trials (P<.001). Adverse events in the raltegravir arm were similar to those reported in the comparator arm.16
Elvitegravir (Gilead) is another integrase inhibitor that is currently in phase 3 clinical trials.17
NNRTIs. Etravirine was approved in January 2008 based on the results of the phase 3 DUET 1 and 2 trials, which were conducted in highly treatment-experienced patients, including those with previous resistance to commercially available NNRTIs. Etravirine twice daily is approved for the treatment of HIV in treatment-experienced patients with previous failure or intolerance to another NNRTI-based regimen.18
Pooled 24-week analysis of the DUET studies indicated that 74% of etravirine-treated patients achieved HIV-1 RNA <400 copies/mL compared with 51.5% of patients receiving OBT alone. At Week 24, the mean decrease in plasma HIV-1 RNA was –2.37 log10 copies/mL in the etravirine treatment arm and –1.68 log10 copies/mL in the OBT arm. The mean increase in CD4+ T lymphocyte count was 81 cells/mm³ in the etravirine treatment arm versus 64 cells/mm³ in the OBT treatment arm.18
Rilpivirine is currently in phase 3 clinical trials for treatment-naïve patients.19 Similar to etravirine, rilpivirine has been demonstrated to have a higher genetic barrier to resistance than first-generation NNRTIs and may be an alternative to efavirenz as an initial NNRTI because of rilpivirine's lower incidence of rash, central nervous system (CNS) disorders, and lipid abnormalities.19,20
HIV TREATMENT GUIDELINES
Guidelines for the use of ARVs in adults and adolescents infected with HIV-1 were developed by a Department of Health and Human Services (DHHS) expert panel and provide guidance to clinicians on when to initiate ARV treatment, preferred and alternative treatment choices and goals, the use of ARVs in special population groups (eg, injection drug users, patients co-infected with hepatitis B virus [HBV] and/or hepatitis C virus [HCV]), and management of the treatment-experienced patient. These guidelines also provide information on standard dosing for ARVs, dose adjustments for patients with renal and hepatic impairment, adverse events, and drug-drug interactions. Separate guidelines are available for the management of HIV infection in adults, adolescents, and children; the prevention of mother-to-child HIV transmission; and postexposure prophylaxis in occupational and nonoccupational settings. This article focuses on pertinent information from the treatment guidelines regarding adult and adolescent patients with chronic HIV-1 infection. The latest update to the guidelines was published on November 3, 2008.21
The DHHS panel strongly recommends obtaining an HIV genotypic resistance assay, which may detect baseline (ie, transmitted) viral resistance mutations and help guide the selection of ARV regimen, before ARV treatment is initiated. This recommendation was implemented after drug-resistant HIV strains (particularly strains resistant to NNRTIs) were detected in up to 15% of patients previously untreated with ARVs.22
The preferred dual NRTI to use in combination with an NNRTI or a PI is tenofovir/emtricitabine. Alternatively, abacavir/lamivudine may be used in patients who test negative for HLA-B*5701 (abacavir hypersensitivity reaction test); zidovudine/lamivudine or didanosine EC combined with emtricitabine or lamivudine can also be used in combination with an NNRTI or a PI.21
The DHHS panel also addresses management of HIV infection in treatment-experienced patients who experience virologic or immunologic failure. Generally, the approach for these patients involves a detailed review of ARV treatment history, past intolerance to ARVs, historical and current resistance assay results, concomitant therapies, and medical conditions. Clinical trials of novel ARVs or treatment approaches for previously treated patients should be considered, if available. Also, when relevant and if available, therapeutic drug monitoring (TDM) for ARVs may be considered.21
ARV ADVERSE EVENTS
Entry inhibitors. Two phase 3 studies demonstrated no increase in mortality or risk of malignancy among patients treated with maraviroc; however, maraviroc-treated patients did demonstrate an increased incidence of cardiac events, herpes, and influenza infections. The most common adverse events reported at a frequency rate higher than that observed with placebo plus OBT were cough, pyrexia, upper respiratory infections, rash, and dizziness.11
The most commonly reported adverse events associated with vicriviroc include nausea, headache, fatigue, anorexia, diarrhea, and abdominal pain.25
Integrase inhibitors. The adverse events reported in >2% of patients treated with raltegravir in the BENCHMRK studies included diarrhea, nausea, headache, and pyrexia. Postmarketing reports of adverse events have included psychiatric disorders, including depression and suicidal ideation/behaviors (particularly in patients with a pre-existing history of psychiatric illness), and skin rash (including Stevens-Johnson syndrome).26
In a study of elvitegravir for treatment-experienced patients, adverse events leading to elvitegravir discontinuation at 24 weeks were similar to those observed in the comparator arm (up to 3% in all arms). Grade 3 and 4 adverse events were reported at a similar rate (up to 14%) in elvitegravir and comparator treatment arms. A higher frequency of grade 3 or 4 adverse events was noted in the elvitegravir 20 mg treatment arm (18%); this treatment dose was subsequently discontinued. Grade 3 or 4 laboratory abnormalities were noted in 21% of elvitegravir-treated patients versus 32% of patients in the comparator arms.27
NNRTIs. The most frequent adverse events reported in >10% of patients treated with etravirine in phase 3 studies included nausea and skin rash. Additionally, GI intolerance (manifested as diarrhea, nausea, abdominal pain, and vomiting), fatigue, headache, peripheral neuropathy, and hypertension were reported at a frequency of ≥2% in etravirine-treated patients in phase 3 studies.18
In a phase 2a clinical trial in 47 HIV-positive, antiretroviral therapy-naïve patients, rilpivirine was well tolerated over 7 days of treatment. The most frequent adverse events (mostly of mild intensity) were GI disorders, which were reported in 25% of rilpivirine-treated patients. Other adverse events occurring in >5% of rilpivirine-treated patients included headache, somnolence, upper respiratory tract infection, fatigue, and eye disorders.28
In a phase 2b dose-ranging trial comparing rilpivirine with efavirenz, the most common adverse events associated with rilpivirine included rash (9% vs 21% in efavirenz arm) and CNS events (31% vs 48% in efavirenz-treated patients).29
HIV treatment outcomes greatly depend on the selection of an effective treatment regimen and the patient's ability to sustain optimal adherence to the regimen. The availability of effective ARVs has contributed to improved quality of life and longer life expectancy. The longer life expectancy introduces a potential for more concomitant therapies and subsequent drug interactions that can be difficult to manage. Generally, most drug interactions with ARVs are either pharmacokinetic or pharmacodynamic. Pharmacokinetic drug interactions involve changes in drug absorption, distribution (protein binding and P-glycoprotein or multidrug-resistant protein-mediated interactions), metabolism (CYP450 enzyme-mediated), and excretion. An example of an absorption-mediated HIV drug interaction is the combination of atazanavir and acid-suppressing agents. Atazanavir requires an acidic pH for adequate absorption; therefore, agents that suppress acid production can impair atazanavir absorption. Another common pharmacokinetic drug interaction pathway involves the hepatic and intestinal CYP450 enzyme system by which NNRTIs, PIs, and maraviroc are metabolized. The NNRTIs efavirenz, nevirapine, and etravirine are known inducers of several CYP enzymes (particularly CYP3A4) and have the potential to reduce plasma levels of concomitant medications, whereas PIs are mostly inhibitors of the same enzyme system (most importantly, CYP3A4). For example, ritonavir is a well-recognized inhibitor of CYP3A4 and is often used in small daily doses (100–400 mg/d) as a pharmacokinetic booster for concomitant PIs. Maraviroc is a substrate of CYP3A4 and P-glycoprotein; therefore, coadministration of maraviroc with inhibitors or inducers of CYP3A4 or P-glycoprotein may increase or decrease maraviroc levels.11,21,30
An example of a pharmacodynamic drug interaction is the combination of stavudine and zidovudine, both thymidine analogues of reverse transcriptase; when coadministered, the combination of zidovudine and stavudine has an antagonistic intracellular activity.
Entry inhibitors. Maraviroc is a substrate of CYP3A4 and P-glycoprotein. When administered with ketoconazole 400 mg/d, the maraviroc area under the curve (AUC) increases 5-fold, and the maximum plasma concentration (Cmax) increases 3.4-fold. When administered with lopinavir 400 mg/ritonavir 100 mg twice daily, the maraviroc AUC increases 3.9-fold, and the Cmax increases 1.9-fold. The dose of maraviroc should be reduced to 150 mg twice daily in the presence of PIs or potent CYP3A4 inhibitors. When administered with rifampin 600 mg/d, the maraviroc AUC and Cmax are reduced by 70%. The dose of maraviroc should be increased to 600 mg twice daily in the presence of CYP3A4 inducers, including efavirenz, rifampin, carbamazepine, phenobarbital, and phenytoin.31
Vicriviroc is a substrate of CYP3A4. Administration of various doses of ritonavir with vicriviroc in healthy volunteers increased the exposure of vicriviroc by approximately 500% regardless of the ritonavir dose. Co-administration of vicriviroc with ritonavir plus efavirenz increased vicriviroc exposure significantly, although not as much as the increase observed with ritonavir alone. Investigators have concluded that vicriviroc may be administered with efavirenz in combination with ritonavir.32,33
Integrase inhibitors. Raltegravir is metabolized by glucuronidation (UDP glucoronosyl transferase 1A1) and does not undergo CYP450-mediated metabolism. In a placebo-controlled study in 12 patients, the combination of raltegravir 400 mg and ritonavir 100 mg twice daily did not affect raltegravir pharmacokinetic parameters.34
Elvitegravir is metabolized via oxidative (CYP3A4) and glucoronidation pathways. This agent is a moderate inducer of CYP3A4 and a substrate of the same enzyme system; its plasma concentration is increased when the CYP3A4 inhibitor ritonavir is coadministered.7 No clinically relevant drug interaction was observed when healthy volunteers received elvitegravir 50 mg/ritonavir 100 mg daily with or without emtricitabine 200 mg/tenofovir 300 mg daily. The combination may be administered without dosage adjustment.35 In another study in healthy volunteers, participants were randomized to receive elvitegravir 200 mg/ritonavir 100 mg once daily, tipranavir 500 mg/ritonavir 200 mg twice daily, or elvitegravir 200 mg once daily plus tipranavir 500 mg/ritonavir 200 mg twice daily for 14 days in a crossover design. Elvitegravir and tipranavir AUC, Cmax, and trough concentrations were similar across treatment groups. No clinically significant drug interactions were observed when elvitegravir and tipranavir/ritonavir were combined.36
NNRTIs. Etravirine is a substrate and inducer of CYP3A4. In a pharmacokinetic study in healthy volunteers, etravirine 1,600 mg twice daily was coadministered with lopinavir 400 mg/ritonavir 100 mg twice daily for 13 days; the coadministration did not lead to significant changes in pharmacokinetic parameters of either drug. Etravirine and lopinavir/ritonavir may be coadministered without dosage adjustment.37 Systemic exposure (AUC) of etravirine was reduced by 33% to 37% when the agent was coadministered with saquinavir/ritonavir or darunavir/ritonavir; however, etravirine can be combined with either of the 2 ritonavir-boosted PIs without any dose adjustment. Etravirine should not be coadministered with tipranavir/ritonavir, as a significant decrease in plasma concentration of etravirine may occur.18
Rilpivirine is an inducer and a substrate of CYP3A4 and has a similar drug interaction profile to commercially available NNRTIs.19 When rilpivirine 150 mg once daily is coadministered with ketoconazole 400 mg, the AUC, Cmax, and Cmin of rilpivirine are increased by 49%, 30%, and 76%, respectively. Ketoconazole AUC, Cmax, and Cmin are decreased by 24%, 15%, and 66%, respectively.38
ADHERENCE TO ARV THERAPY
The goal of ARV therapy is to attain maximal inhibition of HIV replication, reverse immunosuppression, and achieve sustained durability of treatment. One of the barriers to achieving this goal is suboptimal adherence to therapy. Suboptimal adherence can lead to development of viral resistance or cross-resistance to a single ARV drug or a drug class, which subsequently can lead to loss of treatment efficacy. The life-long nature of the treatment, medication-related adverse events, regimen complexity, and pill fatigue are just a few of the obstacles that may lead to suboptimal adherence to HIV therapy. Therefore, it is essential to provide thorough medication and adherence education to patients before they initiate treatment and to reinforce treatment goals as patients initiate and continue to take their ARVs.39
Many support services exist, including pharmacist-based adherence programs. Such programs should be offered to patients whenever they are available. Some HIV clinics offer home-based adherence programs, including directly observed therapy for patients who qualify for this type of service. Additional strategies to sustain good adherence to treatment include managing adverse events, referring the patient to other support services (eg, peer support groups, mental health services), and addressing the confidentiality issues that may interfere with treatment adherence.39–42
In a study published by Paterson et al in 2000,43 an adherence rate of 95% was demonstrated to correlate best with superior virologic outcomes in patients treated with PI-based therapy.
Several methods can be used to measure adherence, including patients' self-reports, pill counts, and evaluation of pharmacy refill patterns. None of these methods is considered a single, best approach to adherence measurement, as they may either overestimate or underestimate a patient's adherence to ARV therapy.39
HIV infection remains a significant public health problem with a substantial effect on morbidity and mortality worldwide. In the United States, management of HIV infection has greatly improved since the advent of HAART and since the introduction of novel treatments with different or superior activity to previously approved treatments. The recent approvals of the CCR5 inhibitor maraviroc, the integrase inhibitor raltegravir, and the latest NNRTI etravirine mark a significant milestone in the treatment of HIV-infected patients, particularly those with limited treatment options resulting from viral resistance or medication intolerance. HIV treatment guidelines regarding these and other ARVs address differences in treatment indications, adverse events, and drug-drug interactions. With all HIV medications-approved or investigational-healthcare professionals continue to face the challenges of drug resistance and treatment adherence.
Dr Stanic is a senior HIV pharmacotherapy specialist, program manager, HIV Specialty Pharmacy Residency, Center for HIV/AIDS Care & Research, Boston Medical Center, and assistant professor of pharmacy practice, Massachusetts College of Pharmacy and Health Sciences, Boston. Dr Grana is an HIV pharmacotherapy specialist, Center for HIV/AIDS Care & Research, Boston Medical Center, and adjunct assistant professor of pharmacy practice, Massachusetts College of Pharmacy and Health Sciences.
Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.
1. Joint United Nations Programme on HIV/AIDS (UNAIDS) and World Health Organization (WHO). AIDS Epidemic Update: December 2007.
2. Celentano DD. Undocumented epidemics of HIV continue to persist in the twenty-first century. AIDS. 2005;19:527–528.
3. Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus (HIV) infection. N Engl J Med. 1998;338:853–860.
4. Levy JA. HIV pathogenesis and long-term survival. AIDS. 1993;7:1401–1410.
5. Alfano M, Poli G. The HIV life cycle: Multiple targets for antiretroviral agents. Drug Design Reviews-Online. 2004;1:83–92.
6. Poveda E, Briz V, Quinones-Mateu M, Soriano V. HIV tropism: Diagnostic tools and implications for disease progression and treatment with entry inhibitors. AIDS. 2006;20:1359–1367.
7. Correll T, Klibanov OM. Integrase inhibitors: A new treatment option for patients with human immunodeficiency virus infection. Pharmacotherapy. 2008;28:90–101.
8. Rana KZ, Dudley MN. Human immunodeficiency virus protease inhibitors. Pharmacotherapy. 1999;19:35–59.
9. Saag M, Ive P, Heera J, et al. A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc vs efavirenz, both in combination with Combivir (zidovudine [ZDV]/lamivudine [3TC]), for the treatment of antiretroviral naive patients infected with R5 HIV 1: week 48 results of the MERIT study. Program and abstracts of the 4th International AIDS Society conference on HIV pathogenesis, treatment and prevention; July 22–25, 2007; Sydney, Australia. Abstract WESS104.
10. Este J, Telenti A. HIV entry inhibitors. Lancet. 2007;370:81–88.
11. Selzentry [package insert]. New York, NY: Pfizer Labs; August 2007.
12. Gulick R, Su Z, Flexner C, et al, and the ACTG 5211 Team. ACTG 5211: Phase II study of the safety and efficacy of vicriviroc (VCV) in HIV-infected treatment-experienced subjects: 48-week results. Presented at: Fourth International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention; July 22–25, 2007; Sydney, Australia. Abstract TUAB102.
13. Stone ND, Dunaway SB, Flexner C, et al. Multiple-dose escalation study of the safety, pharmacokinetics, and biologic activity of oral AMD070, a selective CXCR4 receptor inhibitor, in human subjects [erratum in: Antimicrobial Agents Chemother. 2007;51:3047]. Antimicrobial Agents Chemother. 2007;51:2351–2358.
14. Correll T, Klibanov OM. Integrase inhibitors: A new treatment option for patients with human immunodeficiency virus infection. Pharmacotherapy. 2008;28:90–101.
15. Markowitz M et al. Potent antiviral effect of MK-0518, a novel HIV-1 integrase inhibitor, as part of combination ART in treatment-naïve HIV-1 infected patients. Presented at: 16th International AIDS Conference; August 13–18, 2006; Toronto, Canada. Abstract THLB0214.
16. Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med. 2008;359:339–354.
17. Jones J, Taylor B, Wilkin TJ, Hammer SM. Advances in antiretroviral therapy. Top HIV Med. 2007;15:48–82.
18. Intelence [package insert]. Raritan, NJ: Tibotec Therapeutics; January 2008.
19. Ripamonti D, Maggiolo F. Rilpivirine, a non-nucleoside reverse transcriptase inhibitor for the treatment of HIV infection. Curr Opin Investig Drugs. 2008; 9:899–912.
20. Molina JM, Cordes C, Ive P, et al. Efficacy and safety of TMC278 in antiretroviral-naive, HIV-infected patients: week 96 data from TMC278-C204. Program and abstracts of the 9th International Congress on Drug Therapy in HIV Infection; November 9–13, 2008; Glasgow, United Kingdom. Abstract P002.
21. Panel on Antiretroviral Guidelines for Adults and Adolescents-A Working Group of the Office of AIDS Research Advisory Council (OARAC), Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. November 3, 2008; 1–146. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed January 23, 2009.
22. Kuritzkes DR. Preventing and managing antiretroviral drug resistance. AIDS Patient Care STDS. 2004;18:259–273.
23. Sustiva [package insert]. Princeton, NJ: Bristol-Myers Squibb; March 2008.
24. Rudorf DC, Krikorian SA. Adverse effects associated with antiretroviral therapy and potential management strategies. J Pharm Pract. 2005;18:258–277.
25. Vicriviroc maleate (SCH417690) [investigator's brochure]. Kenilworth, NJ; Schering-Plough; September 2006.
26. Isentress [package insert]. Whitehouse Station, NJ; Merck; October 2007.
27. Zolopa A, Mullen M, Berger D, et al. The HIV integrase inhibitor GS-9137 demonstrates potent antiretroviral activity in treatment-experienced patients. Presented at: 14th Conference on Retroviruses and Opportunistic Infections; February 25–28, 2007; Los Angeles, California. Abstract 143LB.
28. Goebel F, Yakovlev A, Pozniak AL, et al. Short-term antiviral activity of TMC278-a novel NNRTI-in treatment-naive HIV-1-infected subjects. AIDS. 2006;20:1721–1726.
29. Santoscoy M, Cahn P, Gonsalez C, et al. TMC278 (rilpivirine), a next-generation NNRTI, demonstrates long-term efficacy and tolerability in ARV-naive patients: 96-week results of study C204. Presented at: 17th International AIDS Conference; August 3–8, 2008; Mexico City, Mexico. Abstract TUAB0103.
30. Krikorian SA, Rudorf DC. Drug-drug interactions and HIV therapy: What should pharmacists know? J Pharm Pract. 2005;18:278–294.
31. Abel S, Russell D, Ridgway C, et al. Overview of the drug-interaction data for maraviroc (UK-427,857). Presented at: Sixth International Workshop on Clinical Pharmacology of HIV Therapy; April 28–30, 2005; Quebec City, Canada. Abstract 76.
32. Sansone A, Keung A, Tetteh E, et al. Pharmacokinetics of vicriviroc are not affected in combination with five different protease inhibitors boosted by ritonavir. Presented at: 13th Conference on Retroviruses and Opportunistic Infections; February 5–8, 2006; Denver, CO. Abstract 582.
33. Sansone A, Saltzman M, Rosenberg M, et al. Pharmacokinetics of SCH 417690 administered alone or in combination with ritonavir and efavirenz in healthy volunteers. Presented at: Sixth International Workshop on Clinical Pharmacology of HIV Therapy; April 28–30, 2005; Quebec City, Canada. Abstract 79.
34. Iwamoto M, Wenning LA, Petry AA. Minimal effect of ritonavir and efavirenz on the pharmacokinetics of MK-0518. Presented at: 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27–30, 2006; San Francisco, CA. Abstract A-0373.
35. Ramanathan S, Skillington J, Plummer A, et al. Lack of clinically relevant drug-drug interaction between ritonavir-boosted GS-9137 (GS-9137/R) and emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF). Presented at: 16th International AIDS Conference; August 13–18, 2006; Toronto, Canada. Abstract TUPE0080.
36. Mathias A, Hinkle J, Enejosa J, Pillero P, Kearney B. Lack of pharmacokinetic interaction between ritonavir-boosted GS-9137 (elvitegravir) and Tipranavir/r. Presented at: Fourth IAS Conference; July 22–25, 2007; Sydney, Australia. Abstract TuPDB06.
37. Piscitelli S, Baede P, Van't Klooster G, Graham N. TMC125 does not alter lopinavir/ritonavir pharmacokinetics in healthy volunteers. Presented at: 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27–30, 2002; San Diego, CA. Abstract A1824.
38. Van Heeswijk RP, Hoetelmans RM, Kestens D, et al. The pharmacokinetic interaction between ketoconazole and TMC278, an investigational non-nucleoside reverse transcriptase inhibitor in healthy, HIV-negative subjects. Presented at: 16th International AIDS Conference; August 13–18, 2006; Toronto, Canada. Abstract TUPE0087.
39. Hardy H. Adherence to antiretroviral therapy: The emerging role of HIV pharmacotherapy specialists. J Pharm Pract. 2005;18:247–257.
40. Daar ES, Cohen C, Remien R, et al. Improving adherence to antiretroviral therapy. AIDS Read. 2003;13:81–90.
41. Miller LG, Hays RD. Adherence to combination antiretroviral therapy: Synthesis of the literature and clinical implications. AIDS Read. 2000;10:177–185.
42. Vervoort S, Borleffs J, Hoepelman A, Grypdonk, MH. Adherence to antiretroviral therapy for HIV: A review of qualitative studies. AIDS. 2006;21:271–281.
43. Paterson DL, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med. 2000;133:21–30.