Treatment Desired Outcome The central goals of antiretroviral therapy are to decrease morbidity and mortality, improve quality

of life, restore and preserve immune function, and prevent further transmission. The most important and effective way to achieve these goals is maximal suppression of HIV replication, which is interpreted as plasma HIV RNA less than the lower limit of quantitation (i.e., undetectable; usually <50 copies/mL).23 Such a profound reduction in HIV RNA is associated with long-term response to therapy (i.e., durability) as well as increases in CD4 lymphocytes, which closely correlates with the risk for developing OIs. While undetectable HIV RNA almost always corresponds with a rise in CD4 lymphocytes, some patients respond virologically or immunologically without the other. 23 General Approach to Treatment Prior to 1996, HIV infection was treated with one or two nucleoside analog reverse transcriptase inhibitors, which were generally not effective at controlling viremia. Thus, the mainstay of treatment was pharmacologic management of OIs and palliative care. At that time, the prognosis for HIV infection was dire and most patients were disabled and eventually died. In 1995, HIV protease inhibitors (PIs) were introduced followed by non-nucleoside analog reverse transcriptase inhibitors (NNRTIs), and a new paradigm in HIV treatment was born. Combinations of three active antiretroviral agents from two pharmacologic classes were shown to profoundly inhibit HIV replication, prevent and reverse immune deficiency, and substantially decrease morbidity and mortality constituting the ART era.36 At the same time, multiple other major medical advances were introduced, such as the discovery that HIV establishes a longlived reservoir in chronically infected cells, and the viral load test (plasma HIVRNA). With this backdrop of dramatic changes, in 1997 the National Institutes of Health Office of AIDS Research convened a panel to define the scientific principles that might serve as a guide for the clinical use of antiretroviral agents.37 The 11 principles presented here are an amalgamation of knowledge of the life cycle of HIV, the consequences of HIV replication, clinical trials of antiretroviral agents, and scientific opinion. These foundational principles are still relevant today. 1. Ongoing HIV replication leads to immune system damage and progression to AIDS. HIV infection is always harmful, and true long-term survival free of clinically significant immune dysfunction is unusual. 2. Plasma HIV RNA levels indicate the magnitude of HIV replication and its associated rate of CD4 cell destruction, whereas CD4 cell counts indicate the extent of HIV-induced immune damage already suffered. Regular periodic measurement of plasma HIV RNA levels and CD4 cell counts is necessary to determine the risk of disease progression in an HIV-infected individual and to determine when to initiate or modify antiretroviral treatment regimens.
1

3. Because rates of disease progression differ among individuals, treatment decisions should be individualized by level of risk indicated by plasma HIV RNA levels and CD4 cell counts. 4. Use of potent combination antiretroviral therapy to suppress HIV replication to below the levels of detection of sensitive plasma HIV RNA assays limits the potential for selection of antiretroviral-resistant HIV variants, the major factor limiting the ability of antiretroviral drugs to inhibit virus replication and delay disease progression. Therefore, maximum achievable suppression of HIV replication should be the goal of therapy. 5. The most effective means for accomplishing durable suppression of HIV replication is simultaneous initiation of combinations of effective antiHIV drugs with which the patient has not been treated previously and that are not cross-resistant with antiretroviral agents with which the patient has been treated previously. 6. Each of the antiretroviral drugs used in combination therapy regimens always should be used according to optimal schedules and dosages. 7. The available effective antiretroviral drugs are limited in number and mechanism of action, and cross-resistance between specific drugs has been documented. Therefore, any change in antiretroviral therapy increases future therapeutic constraints. 8. Women should receive optimal antiretroviral therapy regardless of pregnancy status. 9. The same principles of antiretroviral therapy apply to both HIV-infected children and adults, although treatment of HIV-infected children involves unique pharmacologic, virologic, and immunologic considerations. 10. Persons with acute primary HIV infections should be treated with combination antiretroviral therapy to suppress virus replication to levels below the limit of detection of sensitive plasma HIV RNA assays. 11. HIV-infected persons, even those with viral loads below detectable limits, should be considered infectious and should be counseled to avoid sexual and drug-use behaviors that are associated with transmission or acquisition of HIV and other infectious pathogens. The extent to which these 11 principles will continue to stand the test of time is unknown; new information on the pathogenesis and treatment of HIV accrues constantly. One continuing source of controversy is whether to treat patients with acute HIV infection. As of December 2009, 25 distinct antiretroviral compounds have been approved by the U.S. Food and Drug Administration (FDA); one (zalcitabine) has since been removed from the market. Table 1344 presents the state of the art for treatment of HIV-infected individuals as of December 2009.23 Treatment is recommended for all HIV-infected persons with a history of an AIDS-defining event, symptomatic disease, or a CD4 lymphocyte count below 350 cells/mm3. Therapy is also recommended for asymptomatic patients with CD4 counts between 350 and 500 cells/mm3, and some clinicians would also favor starting therapy in those with >500 CD4 cells/mm3. Other indications for therapy at any CD4 count include pregnancy, HIV-associated nephropathy, or when treatment is needed for hepatitis B co-infection.

Table 134-4 Treatment of Human Immunodeficiency Virus Infection: Antiretroviral Regimens Recommended in Antiretroviral-NaVe Persons

Preferred Regimens NNRTI based Efavirenz + tenofovir + emtricitabine (AI)

Limitation Not in first trimester of pregnancy or in women without adequate contraception Caution in HCVHBV co-infection, rash

PI based

Darunavir + ritonavir + tenofovir + emtricitabine (AI)

Atazanavir + ritonavir + tenofovir Not with high doses of + emtricitabine (AI) proton-pump-inhibitors, rash Raltegravir + tenofovir + emtricitabine (AI) Twice daily (not once daily) Alternative regimens (some potential disadvantages versus preferred regimens) Efavirenz + (abacavir or zidovudine) + lamivudine (BI) Nevirapine + zidovudine + lamivudine (BI) Possible reduced efficacy for high viral loads (abacavir), more subcutaneous fat loss (zidovudine) Not in moderate to severe hepatic disease or in women with CD4 >250 cells/mm3 or men with CD4 >450 cells/mm3 PI based Atazanavir-ritonavir + (abacavir or zidovudine) + lamivudine (BI) See above

Gastrointestinal Lopinavir-ritonavir (once or twice intolerance, lipids daily) either with (abacavir or zidovudine) + lamivudine or Rash (tenofovir+ emtricitabine) (BI) High number of Fosamprenavir/ritonavir (once or pills/complexity twice daily) either with (abacavir or zidovudine) + lamivudine or (tenofovir + emtricitabine) (BI) Saquinavir-ritonavir (twice daily) + tenofovir + emtricitabine (BI)

Acceptable regimens (potential additional disadvantages or pending additional data) Efavirenz + didanosine + Mitochondrial toxicities (lamivudine or emtricitabine) (CI) with didanosine Atazanavir + (abacavir or zidovudine) + lamivudine (CI) Maraviroc + zidovudine + lamivudine (CIII) Raltegravir + abacavir or zidovudine + lamivudine (Darunavir-ritonavir or saquinavir-ritonavir) + (abacavir or zidovudine) + lamivudine Regimens or components that should not be used Regimen or component Any all NRTI regimen (EI) Abacavir + didanosine or abacavir + tenofovir (DIII) Didanosine + tenofovir (EII) Stavudine (EI) Comment Inferior virologic efficacy Insufficient data Lower atazanavir concentrations compared with atazanavir-ritonavir Lower virologic activity versus efavirenz, need tropism test See above See above

Inferior virologic efficacy, CD4 declines Toxicity including subcutaneous fat loss, peripheral neuropathy, and lactic acidosis Insufficient plasma concentrations and efficacy or not studied

Darunavir or tipranavir or saquinavir without ritonavir (EI) Delavirdine (EII) Enfuvirtide (DIII) Etravirine (DIII)

Inferior virologic efficacy and inconvenient dosing Not studied in nave patients, inconvenient injections Not studied in nave patients

Indinavir with or without ritonavir (EIII) Nelfinavir (without ritonavir) (EI) Ritonavir at virologic doses (EIII) Tipranavirritonavir (EI)

Nephrolithiasis, fluid requirements and inconvenient Inferior virologic efficacy

Gastrointestinal intolerance Inferior virologic efficacy

NRTI, nucleoside reverse transcriptase inhibitor. Evidence-based Rating Definition Rating Strength of Recommendation: A: Both strong evidence for efficacy and substantial clinical benefit support recommendation for use; should always be offered. B: Moderate evidence for efficacy or strong evidence for efficacy but only limited clinical benefit, supports recommendation for use; should usually be offered. C: Evidence for efficacy is insufficient to support a recommendation for or against use, or evidence for efficacy might not outweigh adverse consequences (e.g., drug toxicity, drug interactions) or cost of treatment under consideration; use is optional. D: Moderate evidence for lack of efficacy or for adverse outcome supports recommendation against use; should usually not be offered. E: Good evidence for lack of efficacy or for adverse outcome supports a recommendation against use; should never be offered. Rating Quality of Evidence Supporting the Recommendation: I: Evidence from at least one correctly randomized, controlled trial with clinical outcomes and/or validated laboratory endpoints. II: Evidence from at least one well-designed clinical trial without randomization or observational cohorts with long-term clinical outcomes. III: Evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of consulting committees. a Lamivudine and emtricitabine are considered interchangeable.Adapted from Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. December 1, 2009. http://AIDSinfo.NIH.gov. Sidebar: Clinical Controversy Treatment of persons with acute primary HIV infection with combination antiretroviral therapy to suppress virus replication to levels below the limit of detection of sensitive plasma HIV RNA assays is controversial. Well-designed trials with clinical end points that define the long-term safety and efficacy of initiating combination antiretroviral therapy during acute HIV infection are lacking. Theoretical benefits are decreasing the severity of acute disease; perhaps lowering the initial viral load setpoint, which affects progression rates; preserving immune function; and reducing the risk for viral transmission. However, these potential benefits must be weighed against the issues imposed by early intervention of
5

chronic therapy, which would be many years ahead of normal initiation of therapy (discussed below). The optimal time to initiate therapy in chronic HIV infection has also been a matter of debate over the last 10 years. The relative risk of death in asymptomatic HIV-infected individuals is higher when antiretroviral therapy is delayed. Among individuals with a CD4 count of 351 to 500 cells/mm3 prior to therapy, a 69% increase in the risk of death was found if treatment was deferred until their CD4 cell count fell below 350 cells/mm3 compared to those initiating immediate treatment; similarly, deferring therapy until the CD4 cell count fell below 500 cells/mm3 was associated with a 94% increase in the risk of death.38 Healthcare professionals involved in the care of HIV-infected persons must consult the most current literature on the principles and strategies for therapy. Better patient outcomes are demonstrated when clinicians have significant HIV expertise. Likewise, the patient must be ready and willing to commit to life-long treatment including an understanding of its risks and benefits and the need to maintain a high level of adherence. An excellent source for information on treatment guidelines, which is regularly updated, is available at www.AIDSinfo.NIH.gov. Additional guidelines and electronic resources for HIV clinicians are provided in reference 17. Sidebar: Clinical Controversy The precise time to start therapy is controversial. Early in the ART era, the mantra was "hit early and hit hard," with hopes that the drugs would be well tolerated and the virus could be eradicated. When it became clear that treatment was long term and that these earlier drugs had potential long-term side effects, the mantra changed to a drug-sparing paradigm where therapy was initiated as late as possible. Newer agents have improved upon tolerability, but lack long-term safety data. The benefits of early therapy include preventing the known detriments of unchecked viral replication, including irreversible immune damage and increased likelihood of viral transmission. The potential risks of initiating combination antiretroviral therapy include the lifestyle demands of continuous therapy, drug toxicities, and development of antiretroviral drug resistance. Pharmacologic Therapy Conceptually the four primary methods of therapeutic intervention against HIV are inhibition of viral replication, microbicides to prevent HIV infection, vaccination to stimulate a more effective immune response, and restoration of the immune system with immunomodulators; the latter three approaches are mostly investigational. Several approaches for an HIV vaccine are in development, including whole killed virus, subunit and peptide vaccination, recombinant live vector, and naked DNA delivery. A randomized placebo-controlled trial demonstrated a modest 30% reduction in HIV transmission in a modifiedintention to treat analysis of ALVAC-HIV plus AIDSVAX vaccine in 16,402 volunteers (P=0.04).39 The modified analysis excluded subjects who were found to be HIV-infected prior to randomization. However, the efficacy difference was
6

not significant in the per-protocol analysis (P=0.16). Therefore, the findings must be considered tentative until more definitive data become available. Overall, progress has been slow for the vaccine field. Genetic variability in HIV and a nascent understanding of the role of the immune system in suppressing viral replication are significant barriers to the development of an effective HIV vaccine with long-lasting and protective immunity. Immunomodulators, such as aldesleukin (interleukin 2), provide mild benefits in terms of increased CD4 cells, however, aldesleukin is also associated with significant toxicities and no apparent clinical benefit.40 Additional immunotherapies are in earlier phases of study. Microbicides for use vaginally or rectally to prevent sexual transmission of HIV are in various phases of development.41 Antiretroviral Agents Inhibiting viral replication with combinations of potent antiretroviral agents has been the most clinically successful strategy. Four general classes of drugs are used today: entry inhibitors, reverse transcriptase inhibitors, integrase strand transfer inhibitors and HIV protease inhibitors (Table 1345).23,42,43 Reverse transcriptase inhibitors consist of two classes: those that are chemical derivatives of purine- and pyrimidinebased nucleosides and nucleotides (nucleoside/nucleotide reverse transcriptase inhibitors [NRTIs]) and those that are not (nonnucleoside reverse transcriptase inhibitors [NNRTIs]). NRTIs include the thymidine analogs stavudine (d4T) and zidovudine (AZT or ZDV); the deoxycytidine analogs emtricitabine (FTC) and lamivudine (3TC); the deoxyguanosine analog abacavir sulfate (ABC); and the deoxyadenosine analogs of which didanosine (ddI) is an inosine derivative and tenofovir disoproxil fumarate (TDF) is a deoxyadenosine-monophosphate nucleotide analog (a nucleotide is a nucleoside with one or more phosphates). Note that drug abbreviations are provided here and below for reference, but their use is discouraged because they may lead to prescribing or administration errors. As a class, the NRTIs require phosphorylation to the 5'-triphosphate moiety to become pharmacologically active. Intracellular phosphorylation occurs by cytoplasmic or mitochondrial kinases and phosphotransferases (not viral kinases). The 5'-triphosphate moiety acts in two ways: (a) it competes with endogenous deoxyribonucleotides for the catalytic site of reverse transcriptase, and (b) it prematurely terminates DNA elongation as it lacks the requisite 3'-hydroxyl for sugar-phosphate linking.42 Although NRTI tri-phosphates (or diphosphate for tenofovir) are specific for HIV reverse transcriptase, their adverse effects may be caused in part by inhibition of mitochondrial DNA or RNA synthesis.44 Toxicities include peripheral neuropathy, pancreatitis, lipoatrophy (subcutaneous fat loss), myopathy, anemia, and rarely life-threatening lactic acidosis with fatty liver.45 Use of stavudine and didanosine has declined in favor of more tolerable NRTIs (e.g., emtricitabine, lamivudine and tenofovir).23 With some exceptions, NRTIs are mainly eliminated by the kidney and dose adjustments are required for renal insufficiency. Resistance has been reported for all NRTIs, including cross-resistance within the class as multiple and/or
7

specific mutations accrue.46 Table 134-5 Selected Pharmacologic Characteristics of Antiretroviral Compounds

Drug

F t1/2(h)a Adult Plasma Distinguishing b (% Dose Cmax/Cmin Adverse Effect ) (doses/day ( M) )

Integrase inhibitors (InSTI) Raltegravir ? 9 400 mg (2) 1.74/0.22 Increased creatine kinase Hypersensitivity

Nucleoside (Nucleotide) reverse transcriptase inhibitors (NRTIs) Abacavir 83 1.5/20 300 mg (2) 5.2/0.03 or 600 mg (1) 7.4c Didanosine 42 1.4/24 200 mg (2) 2.8/0.03 Peripheral neuropathy, pancreatitis

or 400 mg (1) 5.6c Emtricitabine 93 10/39 200 mg (1) 7.3/0.04 Pigmentation on soles and palms in non-whites Headache, pancreatitis (children)

Lamivudine

86

5/22

150 mg (2) 6.3/1.6

or 300 mg (1) 10.5/0.5 Stavudine 86 1.4/7 40 mg (2) 2.4/0.04 Lipoatrophy, peripheral neuropathy Renal toxicity (proximal tubule) Anemia, neutropenia, myopathy

Tenofovir Zidovudine

40 85

17/15 300 mg (1) 1.04/0.4 0 2/3.5 200 mg (3) 0.2

or 300 mg (2) 3c Nonnucleoside reverse transcriptase inhibitors (NNRTIs) Delavirdine 85 5.8 400 mg (3) 35/14 Rash, elevated liver function tests

or 600 mg (2) Efavirenz 43 48 600 mg (1) 12.9/5.6 Central nervous system disturbances and teratogenicity Potentially serious rash and hepatotoxicity Rash

Etravirine Nevirapine

? 93

41 25

200 mg (2) 1.69/0.86 Rash, nausea 200 mg (2)d 22/14

Protease inhibitors (PIs) Amprenavire ? 9 1,400 mg (2)e or 1,400 mg (1)e,f 68 7 14.3/2.9 Rash 9.5/0.7

or Forsamprenavir
e

Atazanavir

400 mg (1) 3.3/0.23

Unconjugated hyperbilirubinemi a

or 300 mg (1)f Darunavir 82 15 6.2/0.9

800 mg (1) 11.9/6.5 or 600 mg (2)f 800 mg (3) 13/0.25 or 400800 mg (2)f

Hepatitis, rash

Indinavir

60

1.5 1.5

Nephrolithiasis

Lopinavirg

5.5

800 mg (1) 13.6/7.5 or 400 mg (2) 750 mg (3) 5.3/1.76 or 1,250 mg (2) 7/1.2 16/5

Hyperlipidemia/G I intolerance Diarrhea

Nelfinavir

2.6

Ritonavir

60

35

600 mg (2)d or "Boosting doses"

Gastrointestinal intolerance

Saquinavir

1,000 mg (2)f 500 mg (2)f

3.9/0.55

Mild nausea, bloating

Tipranavir

77.6/35.6 Hepatoxocity, intracranial hemorrhage 1.1/0.73 Injection-site reactions

Entry inhibitorsFusion inhibitor Enfuvirtide 84 3.8 90 mg (2)

Co-receptor inhibitor Maraviroc 33 15 300 mg (2) 1.2/0.066 Hepatitis, allergic reaction

Cmax, maximum plasma concentration; Cmin, minimum plasma concentration; F, bioavailability; t1/2, elimination half-life. aNRTIs: Plasma NRTI t1/2/intracellular (peripheral blood mononuclear cells) NRTI-triphosphate t1/2; plasma t1/2 only for other classes. bDose adjustment may be required for weight, renal or hepatic disease, and drug interactions. cCmin concentration typically below the limit of quantification. dInitial dose escalation recommended to minimize side effects. eFosamprenavir is a tablet phosphate prodrug of amprenavir. Amprenavir is available only as oral solution. fMust be boosted with low doses of ritonavir (100200 mg). gAvailable as coformulation 4:1 lopinavir to ritonavir.Data from Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIVinfected adults and adolescents; December 1, 2009; references 42 and 43, and product information for agents.

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NNRTIs are a chemically heterogeneous group of agents that bind noncompetitively to reverse transcriptase adjacent to the catalytic site. Unlike NRTIs, NNRTIs do not require intracellular activation, do not compete against endogenous deoxyribonucleotides, and do not have potent antiviral activity against HIV-2. Given the different site of binding to reverse transcriptase, NNRTIs can be used with NRTIs effectively. Available NNRTIs include efavirenz (EFV), delavirdine (DLV), nevirapine (NVP) and etravirine (ETR).23 As a class, the NNRTIs are generally associated with rash and elevated liver function tests, including life-threatening cases rarely, particularly for nevirapine.44 NNRTIs tend to have long plasma half-lives and are mainly cleared by liver and/or gutmediated metabolism through the cytochrome P450 enzyme system. The NNRTIs are unique in that a single mutation is needed to confer highlevel cross-resistance for the class (except etravirine), which has been termed a low-genetic barrier to resistance.46 The HIV protease inhibitors (PIs) include amprenavir (APV) and its prodrug fosamprenavir (FPV), atazanavir (ATV), darunavir (DRV), indinavir (IDV), lopinavir (LPV), nelfinavir (NFV), ritonavir (RTV), saquinavir (SQV), and tipranavir (TPV). PIs competitively inhibit the cleavage of the gag-pol polyprotein, which is a crucial step in the viral maturation process, thereby resulting in the production of immature, noninfectious virions. PIs are generally associated with gastrointestinal distress and metabolic changes, such as increased lipids, insulin insensitivity, and changes in body fat distribution.45 PIs are cleared by liver- and gut-mediated metabolism (mainly CYP3A). PIs are almost always used with small doses of ritonavir, a CYP3A inhibitor, to enhance the plasma concentrations of the PI of interest. CYP3A-mediated drug interactions are important considerations for PIs. Resistance to the PIs generally requires the buildup of multiple mutations, termed a highgenetic barrier. Multiple mutations can lead to cross-resistance.46 There are currently two types of entry inhibitors: fusion inhibitors and CCR5 antagonists. Enfuvirtide (ENF) is the only fusion inhibitor available at this time. Enfuvirtide is a synthetic 36-amino-acid peptide that binds gp41, which inhibits fusion of HIV with the target cell. Because of the peptide nature of enfuvirtide, oral delivery is impossible, and subcutaneous injection is the preferred route of administration. Injectionsite reactions are the most common adverse effect. Enfuvirtide is cleared via protein catabolism and amino acid recycling. Enfuvirtide appears to have a low genetic barrier to resistance.46 Maraviroc is CCR5 antagonists. Unlike the other available antiretrovirals which target a viral protein (i.e., enzyme), CCR5 antagonists block a human receptor. The long-term consequences of blocking CCR5 are unknown but may include increased susceptibility to infection by flavivirus (e.g., West Nile virus and tickborne encephalitis virus).47 One advantage of targeting a human receptor is that resistance to CCR5 antagonists may be more difficult to develop. Because CCR5 antagonists are only effective against R5 virus and not X4 virus, a viral tropism assay should be performed prior to using a CCR5 antagonist. Whether long-term use of CCR5 antagonists shifts
11

viral tropism from predominantly R5 to the more pathogenic X4 strain remains to be determined. Maraviroc is a CYP3A substrate; a substrate of P-glycoprotein, thus it is susceptible to drugdrug interactions. Raltegravir is the first integrase strand transfer inhibitor (InSTIs) to be FDA approved and marketed with elvitegravir and other compounds under development. InSTIs bind to HIV integrase while it is in a specific complex with viral DNA. As a result, viral DNA cannot become incorporated into the human genome and cellular enzymes degrade unincorporated viral DNA. Alternatively, recombination and repair mechanisms may form long-terminal repeat (LTR) circular DNA from the unincorporated viral DNA. Raltegravir is primarily glucuronidated by UGT1A1 and is not broadly susceptible to CYP-mediated drug interactions. Elvitegravir is first metabolized by CYP3A then glucuronidated and is thus susceptible to CYP3A drug interactions. Higher elvitegravir plasma concentrations are achieved when coadministered with either low-dose ritonavir or the novel CYP3A inhibitor, cobicistat under development.48 Novel antiviral agents in the classes listed above and novel agents in new drug classes that exploit other steps in the HIV life cycle (see Fig. 1341) are in development, with a focus on activity against drug-resistant virus.49 For example, drugs that block steps in the maturation or assembly of HIV other than protease cleavage are under development. New drugs including cobicistat that increase the plasma concentrations of CYP3A substrates such as PIs are also in development.48 Interestingly, the antimalarials chloroquine and hydroxychloroquine exert antiHIV-1 and antiHIV-2 activity through interference with gp120 (HIV envelope glycoprotein) during assembly.50 The antivirals acyclovir and foscarnet exhibit modest anti-HIV activity via inhibition of HIV reverse transcriptase.51,52 Drug Interactions Medical use of antiretroviral agents is complicated by clinically significant drugdrug interactions that can occur with many of these agents.23,53 Some interactions are beneficial and used purposely (e.g., ritonavir); others may be harmful, leading to dangerously elevated or inadequate drug concentrations. Clinicians involved in the pharmacotherapy of HIV must understand the mechanistic basis for these interactions and maintain a current knowledge of drug interactions for these reasons. Many clinically significant antiretroviral-associated drug interactions involve CYP3A-mediated metabolism and clearance. The PIs, except nelfinavir, the NNRTIs delavirdine and etravirine, the CCR5 antagonist maraviroc, and the InSTI elvitegravir are metabolized by CYP3A. In general, efavirenz, etravirine and nevirapine are inducers of CYP3A, whereas delavirdine and the PIs inhibit CYP3A. Ritonavir is a potent
12

inhibitor of CYP3A-mediated metabolism and is now used almost exclusively at lower doses as a pharmacokinetic enhancer of other PIs.48 Darunavir, lopinavir, saquinavir, and tipranavir must be taken with ritonavir to achieve optimal plasma concentrations. Atazanavir, fosamprenavir, and indinavir are also primarily used with ritonavir for the same reason. Nelfinavir is not effectively boosted by ritonavir given its CYP2C19-mediated metabolism. Many potential concomitant drugs on the market are also metabolized by CYP3A and therefore susceptible to clinically relevant drug interactions with PIs and NNRTIs.23,53 Agents with narrow therapeutic indices and/or that exhibit major changes in pharmacokinetics with CYP3A inhibition are most important in this regard. Examples include, but are not limited to, simvastatin, lovastatin, corticosteroids, ergot derivatives, and some antiarrhythmics. The drug interaction potential of antimycobacterium agents, specifically the rifamycins, are particularly relevant given the high potential for such infections in HIV-infected patients.53 Rifampin, a potent inducer of CYP3A metabolism and conjugation enzymes, is contraindicated with use of most PIs, etravirine, and maraviroc because concentrations are reduced substantially even with ritonavir enhancement. Raltegravir dose should be doubled in the presence of rifampin; efavirenz is an alternative agent. Ritonavir enhancement generally allows coadministration of PIs and rifabutin.53 In such cases, the rifabutin dose will require adjustment given its CYP3A-mediated clearance. The herbal product St. John's wort (Hypericum perforatum) is a potent inducer of metabolism and is contraindicated with PIs, NNRTIs, and maraviroc.23 It must be stressed that the pharmacology of CYP3A interactions may be complicated by simultaneous induction/inhibition of drug transporter-mediated (e.g., P-glycoprotein) clearance and or other phase I or phase II enzymes. Clinicians who treat HIV must stay abreast of antiretroviral drug interaction data. The Department of Health and Human Services guidelines for antiretroviral use provide, and regularly update, excellent summaries of known clinically relevant drug interactions.23,53 NRTIs are not metabolized by CYP3A, but other drug interaction considerations are important. Generally, NRTIs of the same nucleobase should not be coadministered. For example, zidovudine and stavudine are both thymidine analogs and phosphorylated by the same cellular enzymes. Antagonism occurs between these two drugs both in vitro and in vivo; thus, the two should never be given together. Similarly, deoxycytidine analogs should not be coadministered. The deoxyadenosine analogs didanosine and tenofovir exhibit a plasma drug interaction whereby didanosine concentrations are significantly increased.23 Furthermore, the two adenosine analogs are less effective together compared with other recommended NRTI regimens and there is concern for CD4 lymphotoxicity, a troubling effect that appears unique to this NRTI combination. Coadministration of didanosine and tenofovir is not recommended for initial therapy.23

13

Landmarks in the Evolution of Antiretroviral Therapy Antiretroviral therapy has undergone major changes over the past decades. Illustrating these changes is important for a thorough understanding of current treatment strategies. The fundamental landmarks in the use of antiretroviral agents are as follows:

An early study demonstrated that zidovudine monotherapy confers a survival benefit in persons who have AIDS.54 This study showed that a single drug provided moderate clinical benefit. Further investigation showed that combination regimens of two NRTIs (e.g., zidovudine and didanosine or zalcitabine) were superior to zidovudine monotherapy in immunologic and virologic parameters, particularly in patients with no previous antiretroviral therapy, and conferred a superior survival benefit.55 This established that NRTI monotherapy was inferior to dual NRTI therapy. A pivotal study showed that dual NRTI therapy was inferior to triple therapy consisting of 2 NRTIs and the PI indinavir.56 Use of triple therapy with combinations of two NRTIs with NNRTIs or PIs was associated with a durable response as well as significantly reduced incidence of OIs and improved survival, thus establishing the current paradigm of ART. 57 Evolution of triple-therapy regimens with a boosted PI or efavirenz showed superior virologic efficacy versus unboosted PIs and triple NRTI regimens.58,59 Further studies demonstrated that certain ART regimens provided slightly better virologic efficacy, safety/tolerability, and or dosing convenience compared with other three-drug regimens.

Taken together, the pivotal studies described above established that HIV should not be treated with single or dual NRTIs. Current recommendations for initial treatment of HIV infection advocate a minimum of three active antiretroviral agents: Tenofovir disoproxil fumarate plus emtricitabine with either a ritonavir-enhanced PI (darunavir or atazanavir), the NNRTI efavirenz, or the InSTI raltegravir.23 Multiple alternative regimens are also safe and effective, but have one or two disadvantages compared with the preferred regimens, such as weaker virologic responses with high viral loads, lower tolerability, or greater risk of long-term toxicities such as subcutaneous fat loss. Preferred and alternative antiretroviral regimens are listed in Table 1344.23 The World Health Organization (WHO) also updated its treatment recommendations for resource-limited settings. The main updates to the WHO guidelines are the recommendation to treat at higher CD4 count thresholds (350 cell/mm3) and not to include stavudine as initial therapy.60 A great number of considerations go into choosing the optimal drug regimen for a given patient. A resistance test is generally recommended
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when the patient enters HIV care and the results should help guide therapy. Other considerations include avoidance of PIs in patients taking contraindicated concomitant medications such as rifampin (efavirenz would be an alternative), avoidance of tenofovir in patients with preexisting renal dysfunction (abacavir would be an alternative), and avoidance of efavirenz in fertile women not on stable and reliable contraception (PIs would be an alternative). The most convenient regimen is a once-daily fixed-dose combination formulation of efavirenz tenofovir disoproxil fumarateemtricitabine. Other antiretrovirals are also available in fixed-dose combinations to minimize the number of pills required per dose. Several factors contribute to whether the patient will mount a durable response to initial therapy, including adherence, pharmacologic effectiveness, and tolerability. The simplest definition of adherence is the patient's ability to take medication as directed. Antiretroviral therapy is complex and long term, and the risk for virologic failure increases as adherence decreases.61 As clinicians, it is critical to establish a relationship of trust with the patient and to communicate to the patient the importance of proper medication taking. Education should be aimed at understanding the disease process, monitoring, and goals of therapy. An individual's "readiness" to take medications should be clearly established before any treatment is initiated.23 Help from caregivers, friends, and/or family members should be leveraged by the patient because social and psychological support are among the most important factors that influence adherence in this patient population. Based on clinical trial data, approximately 70% to 90% of patients will achieve undetectable viral loads with modern ART regimens. Tenofovir disoproxil fumarate and emtricitabine (tenofovir-emtricitabine) has emerged as the preferred NRTI combination.6265 An open-labeled trial of 517 antiretroviral nave patients randomized to tenofovir-emtricitabine versus zidovudine-lamivudine both with efavirenz demonstrated that significantly more patients in the tenofovir-emtricitabine arm achieved less than 400 copies/mL of HIV-RNA at 48 weeks (84%) compared with patients randomized to zidovudine-lamivudine (73%).63 CD4 increases were also significantly greater in the tenofovir-emtricitabine versus zidovudine-lamivudine group. Part of this difference was attributed to more patients discontinuing zidovudine-lamivudine due to adverse events compared with tenofovir-emtricitabine. Subcutaneous fat loss and lipid elevations were also higher in the zidovudine- lamivudine group through 48 weeks. A slight decrease in glomerular filtration rate was observed in the tenofovir-emtricitabine group versus a slight increase in the zidovudine-lamivudine group. Another randomized study compared abacavir-lamivudine to tenofovir-emtricitabine in a blinded manner in combination with either efavirenz or atazanavir/ritonavir (open labeled) in 1858 antiretroviral nave adults. Among subjects with >100,000 copies/mL of plasma HIV-RNA at screening, those randomized to abacavir-lamivudine experienced twice the virologic failure rate and significantly more adverse events compared with those randomized to
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tenofovir-emtricitabine.66 Other studies have also evaluated virologic efficacy and safety of abacavir-lamivudine in subjects with >100,000 copies/mL at baseline and have found high rates of efficacy and safety regardless of baseline viral load.67 Taken together, these studies have solidified tenofovir-emtricitabine as the first line NRTI combination, as well as efavirenz-tenofovir-emtricitabine as a first line regimen for antiretroviral nave patients. The STARTMRK study was a randomized, placebo-controlled, multicenter comparison of efavirenz versus raltegravir, both with tenofoviremtricitabine, in 566 antiretroviral nave adults.62 In the intent-to-treat analysis, 86% of subjects had <50 copies/mL at 48 weeks in the raltegravir group versus 82% of subjects in the efavirenz group (noninferiority P<0.0001). The mean CD4 increase at week 48 was 189 and 163 cells/mm3, respectively (P=0.02), and the time to reach <50 copies/mL was faster in the subjects randomized to raltegravir. About half as many subjects randomized to raltegravir had an adverse effect of moderate-to-severe intensity compared with those randomized to efavirenz. This study led to the inclusion of raltegravir-tenofovirefavirenz as a preferred regimen for initial treatment of HIV-infection. The ARTEMIS trial was a noninferiority, open-labeled, randomized study of darunavir-ritonavir once daily versus lopinavir-ritonavir either once or twice daily all in combination with tenofovir-emtricitabine in 689 antiretroviral nave adults.64 At week 48, 84% versus 78% of subjects had HIV-RNA levels <50 copies/mL in the darunavir-ritonavir and lopinavirritonavir groups, respectively (noninferiority P<0.001). CD4 responses were similar between the two groups, however, the virologic response was higher for darunavir-ritonavir in those with >100,000 copies/mL of HIV-RNA at baseline. More subjects in the lopinavir-ritonavir group experienced gastrointestinal intolerance and lipid elevations. The CASTLE study was another noninferiority, open-labeled, randomized trial that compared atazanavir-ritonavir to lopinavir-ritonavir (twice daily) both with tenofovir-emtricitabine in 883 antiretroviral-nave adults.65 At 48 weeks, 78% and 76% of subjects in the respective groups achieved <50 copies/mL (noninferiority P<0.001). CD4 responses were similar in the two groups as were responses in subjects with high viral loads at baseline. More subjects in the lopinavir-ritonavir group experienced gastrointestinal intolerance and high lipids whereas more subjects in the atazanavir-ritonavir group experienced asymptomatic hyperbilirubinemia from atazanavir's inhibition of UGT1A1. These studies established darunavir-ritonavir and atazanavir-ritonavir both with tenofovir-efavirenz as preferred first-line regimens for HIV-infection and, along with other studies, moved lopinavir-ritonavir to an alternative regimen.68 Patients with sustained undetectable HIV-RNA taking out-of-date drug regimens may be candidates to simplify to one of the preferred regimens or a more desirable alternative regimen based on past treatment history and other variables. If abacavir is to be used in any regimen, a test for the
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presence of human leukocyte antigen (HLA) B*5701 should be done as its presence has been strongly correlated with the development of abacavir hypersensitivity. Should this test be positive, an abacavir allergy should be added to the patient's chart and abacavir should not be used in the patient. Similarly, a tropism test is required prior to using maraviroc to establish that the patient's virus uses the CCR5 co-receptor.23 Finally, because of the risk of side effects and resistance associated with NRTIs and NNRTIs, several trials have assessed ritonavir boosted PI monotherapy. In general, this strategy is inferior to three drug regimens unless the patient has been virologically suppressed for at least 6 months.69 Ritonavir-boosted PI monotherapy cannot be advocated at this time.23 Resistance Regimen failure is commonly associated with antiretroviral resistance, and testing for such resistance is a useful clinical tool.46 The two types of resistance tests available are phenotype and genotype. A phenotype test determines the concentration of antiretroviral necessary to inhibit 50% replication of the patient's viral isolate (inhibitory concentration of 50% [IC50]) in a recombinant in vitro viral assay. Results usually are expressed as a fold change in susceptibility (IC50) compared with a wild-type laboratory strain virus. Generally, the fold-change in IC50 increases as HIV accumulates additional mutations that confer resistance to a particular drug. However, a single mutation may confer a very high fold-change in IC50 for some drugs (e.g., lamivudine, emtricitabine, efarvirenz, nevirapine) rendering them ineffective after a single mutation. Although small to moderate increases in the fold change suggests reduced susceptibility to that antiretroviral agent, resistance may not be absolute, and partial susceptibility may remain. Theoretically, drug levels may be increased to overcome reduced susceptibility; this strategy is currently under evaluation. The strengths of phenotypic testing is to provide resistance information for complex mutation patterns, but it is also associated with higher cost, limited number of commercial providers, and slower turnaround time for results. Genotyping assesses genetic mutations and associated codon changes in gp41, reverse transcriptase, integrase or protease in the patient's virus and compares it to the wildtype sequence. Mutations, when present, are listed by the wild-type amino acid followed by the position in the genetic sequence of the protein or enzyme and end with the mutation found in the patient. For example, a common mutation caused by lamivudine and emtricitabine is the M184V mutation: a substitution of valine (V) for methionine (M) at the 184 position of reverse transcriptase. Mutations can confer varying degrees of antiretroviral drug resistance and in some cases, weighting algorithms have been developed to predict the relative impact of mutation combinations on antiretroviral activity. Algorithms have also been developed to predict a phenotype from a genotype test (i.e., virtual phenotype). Not all mutations, however, are only detrimental for example, while M184V confers significant resistance to lamivudine and
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emtricitabine, it is also associated with a less fit virus.70 New genetic mutations are discovered occasionally and interpretation of genotypes resistance tests is complex, therefore the reader is encouraged to consult the most recent guidelines on HIV resistance testing.46 Treatment of Special Populations Pregnancy Several considerations are relevant to the treatment of pregnant women, including the health of the mother, prevention of HIV transmission to the fetus, potential for teratogenicity, and dosing issues based on pharmacokinetic changes during pregnancy. Treatment recommendations should be consulted to address the specific requirements for HIV-infected pregnant women and the prevention of vertical transmission.11 Generally, pregnant women should be treated as would nonpregnant women, with some exceptions. For example, efavirenz should not be used, particularly in the first trimester, because of potential teratogenicity. Zidovudine prophylaxis is generally recommended as part of treatment regimens based on early studies demonstrating clear prophylactic effectiveness as well as extensive familiarity with the side-effect profile.11 Infants also receive zidovudine prophylaxis for 6 weeks after birth. Lopinavir-ritonavir has also been studied extensively in pregnant women, and is recommended in this population. Currently, HIV transmission rates have been reduced to <2% for women who are treated with ART and when zidovudine prophylaxis is used.11 In resource-limited settings or when HIV infection is detected very close to delivery, an abbreviated course of zidovudine (i.e., given during labor or in the first 48 hours of the baby's life) also can reduce transmission substantially and may be easier for the patient to take. Alternatively, single-dose nevirapine given to the mother during labor and to the baby within 3 days of birth can reduce transmission of HIV; however, the risk of nevirapine resistance in the mother is considerable (and in infants who become HIV-infected), occurring in nearly 60% of cases.71 The high risk likely is due to the low genetic barrier to resistance for nevirapine coupled with the long decay half-life and subsequent prolonged suboptimal concentrations. Resistance from single-dose nevirapine in mothers can be reduced from approximately 60% to 9% with the addition of 4 to 7 days of zidovudine-lamivudine.71 Postexposure Prophylaxis Protection of healthcare workers from accidental exposure to HIV and in cases of rape or high-risk postcoital and postinjection drug-use episodes are important concerns. The CDC has issued guidelines governing treatment of occupational and other high risk HIV exposures.7,10 These guidelines should be consulted for updates as the knowledge in this field evolves. The principles of the guidelines are to grade the exposure risk and treat as soon as possible after high-risk exposures to prevent HIV infection. The makeup of the treatment depends upon the risk. Postexposure prophylaxis (PEP) with a triple-drug regimen consisting of two NRTIs and a boosted-PI is recommended for percutaneous blood exposure involving significant risk (e.g., large-bore needle, visible blood from patients with advanced AIDS). Two NRTIs may be offered to the healthcare worker with lower risk of exposure, such as cases involving superficial exposures to the mucous membrane or broken skin. Urine, saliva, nasal secretions,
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stool, and sputum are not considered infectious unless visibly contaminated with blood. The optimal duration of treatment is unknown, but at least 4 weeks of therapy is advocated. Treatment ideally should be initiated within 1 to 2 hours of exposure, but treatment is recommended up to 72 hours postexposure. Expert consultation is needed when exposure to drug-resistant virus is suspected or confirmed, but this should not delay initiation of postexposure prophylaxis.7,10 Preexposure prophylaxis (PrEP) is under phase III study for reducing HIV transmission. The concept is to prevent HIV infection by treating persons at high risk for HIV exposure with antiretrovirals before they are actually exposed. Tenofoviremtricitabine are the agents under most study at this time. However, this strategy cannot be recommended until safety and efficacy information become available.

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