Anti Retro Viral Drugs Classification

Antiretroviral Drugs Classification & Highly Active Anti-Retroviral Therapy (HAART) Antiretroviral therapy (ART) is treatment of people infected with human immunodeficiency virus (HIV) using anti-HIV drugs. The standard treatment consists of a combination of at least three drugs (often called highly active antiretroviral therapy or HAART) that suppress HIV replication. o Three drugs are used in order to reduce the likelihood of the virus developing resistance. o ART has the potential both to reduce mortality and morbidity rates among HIV-infected people, and to improve their quality of life.

1. Nucleoside & nucleotide reverse transcriptase inhibitors (NRTIs) Virustatic Block the RNA-dependent DNA polymerase - reverse transcriptase, from synthesizing viral cDNA from HIV RNA. Drugs from this class were the first antiretrovirals to enter clinical use, but because of drug associated toxicities, these early agents have largely been replaced in clinical practice by newer drugs with improved therapeutic, toxicity, and dosing profiles. All drugs in this class are analogues of native nucleotides. o and almost all of them share the common motif of a lack of 3-OH group on their ribose ring: prevents the addition of nucleotides to the elongating proviral DNA strand; this effectively terminates proviral DNA synthesis (Fig. 128-2, Table 128-1). The structural exception is tenofovir: o causes chain termination due to the lack of an intact ribose moiety. Drugs in this class must be phosphorylated by intracellular kinases into their active triphosphate form before they can effectively inhibit reverse transcriptase, o and all of these agents can, to a much lesser extent, inhibit the activity of normal cellular DNA polymerases most notably the mitochondrial DNA polymerase- (pol-). o This NRTI-associated inhibition of mitochondrial function and replication accounts for certain drug-specific adverse effects, such as: hyperlactatemia, lactic acidosis, hepatic steatosis, peripheral neuropathy, myopathy, and lipoatrophy. The dideoxynucleoside RT inhibitors exhibit the tightest binding to and the most inefficient exonucleolytic removal (proofreading) from DNA pol-; o this leads to the greatest degree of mtDNA synthesis inhibition via chain termination.4-6 The rank order of NRTIs associated with mitochondrial dysfunction is: o dideoxyinosine (ddI) > stavudine (d4T) > zidovudine (ZDV) >> lamivudine/emtricitabine (3TC/FTC) = abacavir (ABC) = tenofovir (TDF). Lamivudine, emtricitabine, abacavir, and tenofovir are the NRTIs least likely to be associated with adverse drug effects resulting from mitochondrial dysfunction. Description a thymidine analogue that is administered orally as a 300-mg pill twice daily. o More commonly, however, zidovudine is co-formulated with lamivudine and administered twice daily. For patients with renal impairment necessitating peritoneal-/hemodialysis or continuous venovenous hemofiltration, zidovudine dosing should be adjusted to 100 mg every 8 hours. Zidovudine can be taken with or without food and has an oral bioavailability of 64%, in part due to first-pass glucuronidation in the liver. Zidovudine is neither a substrate for nor an inducer of the cytochrome P-450 (CYP450) enzyme complex. The short plasma half-life and concentrations of zidovudine do not accurately reflect the more robust intracellular concentrations of the zidovudine-phosphorylated forms. Zidovudine should never be co-administered with stavudine (d4T) because of antagonism, demonstrated both in vitro and in vivo.7,8 As the first antiretroviral agent approved in the United States in 1987, a wealth of clinical outcomes data have been generated with zidovudine as either monotherapy or dual therapy.9-13 The use of zidovudine in effective three-drug regimens has been systematically evaluated since 1996.14 o A study that compared the efficacy of six combination regimens demonstrated the superiority of zidovudine in combination with lamivudine and efavirenz and established this zidovudine- containing regimen as the standard for initial antiretroviral therapy at the time.15 o Since then, however, tenofovir-containing regimens have largely replaced zidovudine-containing regimens as the preferred first-line regimens because of superior virologic outcomes, reduced drug resistance, and less lipoatrophy.16,17 Current recommendations of various guidelines panels list zidovudine in combination with lamivudine as an alternative nucleoside backbone choice if the preferred tenofovir-containing regimens cannot or should not be used.18 Zidovudine, used as monotherapy or in combination, has also been widely used to prevent maternal-to-child transmission of HIV; rates of transmission in the United States and many other countries are now less than 2%, often utilizing zidovudine-containing regimens.19-21

Agents Zidovudine

Didanosine

The most common adverse effects of zidovudine are headache and malaise. o Other common side effects include anorexia, nausea, and vomiting. o These symptoms often improve during the first month of therapy. o Zidovudine can also cause dose-limiting toxicities of anemia and granulocytopenia. Of greatest long-term concern is the interference of zidovudine with the normal function of mitochondrial DNA pol-. o Lactic acidosis, o hepatic steatosis, o peripheral neuropathy, o lipodystrophic/ lipoatrophic changes, o and myopathy o all appear to be related to the mitochondrial toxicities associated with zidovudine. Because of fewer toxicities and superior clinical outcomes observed with newer NRTIs, o zidovudine is no longer frequently used as a firstline antiretroviral agent in developed countries. o However, the combination of zidovudine and lamivudine remains first-line therapy for HIV-infected pregnant women. Two resistance pathways have been described in patients failing zidovudine (or stavudine) therapy, most often when used as monotherapy or dual therapy in the prehighly active antiretroviral therapy (HAART) era. Thymidine analogue mutations (TAMs) accumulate in the reverse transcriptase gene at either positions 41, 210, and 215 (TAM1 pathway) or positions 67, 70, and 219 (TAM2 pathway). Although the factors responsible for the emergence of one pathway over the other are unclear, o the TAM1 pathway confers higher-level zidovudine resistance and greater cross-resistance to other NRTIs than does the TAM2 mutation pathway. Mutations from both pathways can be seen in patients, and TAMs can continue to accumulate over time, especially in those who continue zidovudine in the presence of either a partially suppressive or overtly failing regimen. functionally an adenosine analogue that is administered in a delayed-release enteric-coated form. Dosing is weight based: o 400 mg daily is recommended for patients who weigh 60 kg or more, o and 250 mg is recommended for patients who weigh less than 60 kg. In the setting of renal insufficiency, didanosine dosing should be reduced commensurate with creatinine clearance. There is no specific recommendation for dosing in the setting of hepatic impairment, although the potential for toxicities in this situation should be closely monitored. Didanosine absorption is decreased in the presence of food, and the drug should be taken 30 minutes before or 2 hours after a meal. Administration of ganciclovir, allopurinol, and tenofovir increases didanosine concentrations, whereas methadone decreases the didanosine area under the curve (AUC).25 Clinically, didanosine has been used throughout the pre- and post-HAART eras with some success. Didanosine-based regimens are often considered alternatives in guideline recommendations.18,26 Data from the ACTG 5175 trial demonstrated an inferior virologic response in participants receiving a regimen of didanosine, emtricitabine, and unboosted atazanavir compared to participants taking either zidovudine/lamivudine or tenofovir/emtricitabine with efavirenz. As with other dideoxynucleotides, didanosine may be associated with mitochondrial associated toxicities. o Most commonly, didanosine can cause: peripheral neuropathy and pancreatitis and should not be coadministered with drugs that have similar toxicity profiles (e.g., ethambutol, isoniazid, and pentamidine). In one observational study, current didanosine use was associated with a reversible 1.5-fold increased relative risk of myocardial infarction (MI), even after adjustment or baseline cardiovascular risk.27 o This corresponds to an absolute increase of 1.5 MIs per 1000 patient-years in patients taking didanosine. o Six months after didanosine was discontinued, the MI rates were similar to those in patients who had never received didanosine. o However, these data were not confirmed in a second study.28 Didanosine resistance during the mono- and dual-therapy era was most often conferred by the L74V mutation in the RT gene. o In the era of combination therapy, this mutation is less commonly seen. o Resistance to didanosine can also be conferred by point mutations that confer broad class resistance across the NRTIs.

Stavudine

Lamivudine/ Emtricitabine

Abacavir

These include the 69 insertion complex and the Q151M complex.29 o Didanosine can also select for the signature tenofovir mutation K65R in vitro, although the significance of this in vivo is unknown.30 a thymidine analogue dosed at 40 mg twice daily for patients weighing more than 60 kg; o a dose reduction to 30 mg twice daily is recommended for patients weighing less than 60 kg. Stavudine has similar antiretroviral activity as zidovudine, but it has significant toxicities that limit its clinical use, including: o peripheral neuropathy, o hyperlactatemia, o lactic acidosis, o hepatic steatosis, o lipoatrophy, o and pancreatitis. Stavudine is antagonistic to zidovudine and should not be co-administered with didanosine because of concerns for potentially fatal lactic acidosis that appears to have a female predominance.22 o In one clinical trial, participants randomized to receive stavudine in their antiretroviral regimen developed lower amounts of limb fat than participants receiving either zidovudine or tenofovir.23 Stavudine offers no advantages in virologic outcome over tenofovir and should not generally be used as first-line antiretroviral therapy.24 o Nevertheless, because of co-formulation with other agents and cost concerns, it is still widely used as part of initial regimens in the developing world. a cytosine analogue with activity against HIV and hepatitis B virus (HBV). Emtricitabine is chemically related to lamivudine. o Given their similar activities and toxicities, these drugs are discussed together. o Importantly, however, these drugs should not be used together clinically. Lamivudine and emtricitabine can be taken with or without food and require dose reductions in patients with renal insufficiency. These drugs have minimal DNA pol- inhibitory effects. Lamivudine or emtricitabine forms part of the backbone of nearly all currently recommended antiretroviral regimens. Emtricitabine is available as a fixed-dose combination: o with tenofovir o or with tenofovir and efavirenz. Lamivudine is available co-formulated with: o abacavir o or zidovudine, o or both. No direct comparisons of lamivudine and emtricitabine have been performed, although emtricitabine and lamivudine are often included as parts of combination regimens that are being compared. In general, regimens with an emtricitabine/tenofovir NRTI backbone have outperformed regimens with a idovudine/lamivudine backbone.16 Lamivudine and emtricitabine are each well tolerated. Headache,nausea, fatigue, and neutropenia have been reported. Care should be taken when discontinuing lamivudine or emtricitabine in patients coinfected with HBV because HBV rebound and worsening hepatitis can occur. High-level resistance to lamivudine and emtricitabine, up to 1000-fold, is conferred by a point mutation at position 184 in the RT gene (M184V). o This mutation comes with a fitness cost to HIV that results in a 0.3 to 0.6 log10 reduction in plasma HIV RNA levels.31,32 o This fitness cost to HIV is often exploited clinically by continuing lamivudine or emtricitabine therapy in patients harboring virus with the M184V mutation. o M184V can also: hypersensitize HIV to inhibition by zidovudine, restore sensitivity to zidovudine in the presence of TAMs,33 and delay or prevent the emergence of TAMs.31 a synthetic guanosine analogue administered orally: o either 300 mg twice daily

Tenofovir

or 600 mg once daily. Mild hepatic dysfunction necessitates a decrease in dose to 200 mgtwice daily; the use of abacavir in patients with moderate to severe hepatic dysfunction is contraindicated. The use of abacavir with ribavirin or ganciclovir can increase the likelihood of mitochondrial,hepatic, and pancreatic toxicities. Abacavir is not a substrate or inhibitor of the CYP450 enzyme complex, can be taken with or without food, and is metabolized primarily by glucuronidation. Abacavir is available as fixed-dose combinations with: o lamivudine o and with lamivudine and zidovudine. In abacavir-nave patients with plasma viral loads less than 50copies/mL, the substitution of abacavir for either zidovudine or stavudine: o maintained virologic suppression at 1 year o and improved total cholesterol and triglyceride levels.34 A previous study demonstrated that substitution of either abacavir or tenofovir for stavudine or zidovudine in patients with lipoatrophy led to significant gains in limb fat.35 On the basis of clinical trials, abacavir/lamivudine is considered either a preferred nucleoside backbone combination for antiretroviral nave patients or an alternative combination in this population.18,36 Preliminary results from the ACTG 5202 trial that compared tenofovir/emtricitabine to abacavir/lamivudine, in combination with either efavirenz or ritonavir-boosted atazanavir, demonstrated reduced virologic responses in participants with high initial viral loads (>100,000copies/mL) who were randomized to receive abacavir/lamivudine.37 o However, a similarly designed, albeit smaller, study also comparing abacavir/lamivudine with tenofovir/emtricitabine showed no differences in responses among individuals with high initial viral loads.38 In another trial in treatment-nave subjects, the addition of abacavir to a three-drug regimen of zidovudine, lamivudine, and efavirenz did not improve treatment results.39 Abacavir is a weak inhibitor of DNA pol- and exhibits few mitochondrial-associated toxicities. The most significant acute adverse effect of abacavir use is a potentially fatal hypersensitivity syndrome. o The presence of fever, abdominal pain, and rash, usually within 2 weeks of starting abacavir, generally requires discontinuation of the drug. o This syndrome has been linked to the presence of the HLAB*5701 allele, found in 5% to 8% of white HIV-infected populations. Screening for the HLA-B*5701 allele led to reductions in both clinically diagnosed and immunologically confirmed hypersensitivity reactions, and screening is now recommended prior to considering abacavir therapy.40 Patients who are HLA-B*5701 positive should not receive abacavir. Data from two large cohort studies have raised concerns about possibly increased rates of MI in patients taking abacavir. o The D:A:D study group found a 1.9-fold increased relative risk of MI in patients with recent or current abacavir use (absolute risk increaseof 3.5 MIs per 1000 patientyears); this decreased to baseline risk 6 months after abacavir discontinuation.27 o The SMART study investigators also assessed MI risk and found an increased risk of cardiovascular events in participants with five or more cardiovascular risk factors who received abacavir.28 o However, evaluation by the pharmaceutical manufacturer of abacavir of patients on clinical trials of this agent did not demonstrate a higher than expected rate of MIs.41 Reduced phenotypic susceptibility and resistance to abacavir can be conferred by the RT gene mutations K65R, L74V, Y115F, and M184V.42 o L74V reduced abacavir susceptibility twofold, K65R roughly threefold, and Y115F threefold, whereas the M184V mutation in isolation did not reduce abacavir activity unless paired with more than two TAMs.43-46 o The combination of M184V with either L74V or K65R resulted in a five- to eightfold decrease in abacavir susceptibility. As is the case for other NRTIs, high-level abacavir resistance accompanies the Q151M complex and T69 insertion mutations. Tenofovir is a nucleotide adenosine 5-monophosphate derivative because of poor oral bioavailability, is commercially available as the prodrug tenofovir disoproxil fumarate (TDF). Tenofovir has activity against both HIV and HBV, and it is administered orally at a dose of 300 mg once daily without regard to food; it is also available as fixed dose combinations with: o emtricitabine, o as well as with emtricitabine with efavirenz. Dosing o should be decreased in patients with renal insufficiency;

o o

Zidovudine + lamivudine Abacavir + lamivudine Tenofovir + emtricitabine Zidovudine + lamivudine + abacavir Tenofovir + emtricitabine + efavirenz

o no dose adjustment is needed for hepatic impairment. After ingestion, TDF is hydrolyzed to tenofovir, and then it is phosphorylated and incorporated into HIV DNA, causing chain termination. Tenofovir has low affinity for cellular DNA polymerases, including the mitochondrial DNA pol-. The majority of tenofovir is excreted unchanged in the urine via glomerular filtration, although the drug is also actively secreted across the renal tubule. Tenofovir is not a substrate for or inducer of the CYPs, o but it can reduce atazanavir concentrations; o ritonavir and atazanavir increase tenofovir exposure. Tenofovir and didanosine should not be co-administered. Tenofovir is o now included in many preferred first-line antiretroviral regimens, o and it can also be used in treatment-experienced patients whose virus lacks the K65R mutation. Tenofovir, in combination with either lamivudine or emtricitabine, is often used in patients co-infected with HIV and HBV. In general, regimens that include a nucleoside backbone of tenofovir and either emtricitabine or lamivudine, along with either a boosted protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI), are likely to achieve durable HIV responses.16,47-50 o There are exceptions to this rule. Some patients receiving tenofovir in combination with emtricitabine (or lamivudine) and nevirapine have experienced early virologic failure,51 and certain triple-nucleoside combinations that include tenofovirfor example, tenofovir/lamivudine/abacavir and tenofovir/lamivudine/didanosinehave fared less well than some comparator regimens.52 The triple-NRTI combination of tenofovir/zidovudine/lamivudine has antiviral activity but has never been compared directly with more standard regimens.53 There has been some concern about the cumulative nephrotoxic potential of tenofovir given its structural similarity to the nephrotoxic nucleosides adefovir and cidofovir. o Cases of renal dysfunction in patients taking tenofovir have been reported.54,55 o In an observational cohort, the use of tenofovir was associated with a greater decline in renal function than was seen with other NRTIs.56 o Decreased glomerular filtration rates in patients receiving tenofovir were modest within 6 months of starting therapy (14 mL/min per 1.73 m2) and appeared to stabilize after 18 months (glomerular filtration rate [GFR] decline of 19 mL/min per 1.73 m2); o these findings were not associated with an increased rate of tenofovir discontinuation.57 o Tenofovir, in combination with boosted PIs, was associated with greater declines in renal function compared to tenofovir in combination with NNRTIs, although it is not always clear that observed decreases in GFR on tenofovir are clinically significant.58 o Given the relatively short periods of follow-up in these studies, monitoring of renal function in patients receiving tenofovir (serum creatinine, urinalysis, and urine electrolytes) is warranted. Resistance to tenofovir is selected by the K65R mutation and confers a twofold reduction in tenofovir activity. The TAM1 pathway (41L, 210W, 215Y/F) reduces tenofovir susceptibility fourfold, o whereas the TAM2 pathway has less of an effect on tenofovir activity.29,59,60 Insertion mutations at position 69 confer high-level resistance to the NRTIs including TDF, whereas tenofovir retains significant activity in the presence of the Q151M complex.61-63

Multi-class combination products

2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind reverse transcriptase but, in contrast to NRTIs, do so in a pocket far from the active site (Fig. 128-3, Table 128-2). NNRTIs are noncompetitive inhibitors that induce conformational changes in reverse transcriptase, thereby reducing its activity. Available NNRTIs: o have long half-lives (T1/2 25 to 55 hours), o do not require phosphorylation, o and are HIV-1 specific; they have no activity against HIV-2. The NNRTI binding pocket on RT is nonessential to enzymatic function and can tolerate mutations without significant loss of RT activity. NNRTIs are hepatically metabolized and are substrates for the CYP enzymes. o The potential for clinically relevant drug-drug interactions is therefore higher in NNRTIs than in NRTIs. The barrier to HIV-1 resistance is low for NNRTIs. o Single point mutations in RT can inactivate all members of this class, with the exception of etravirine. o Given this low resistance barrier, NNRTIs are often used early in therapy when the probability of HIV resistance to these agents is lowest and the combined protective effect of three fully active drugs is maximized. Agents Description Nevirapine is administered orally with or without food at 200 mg once daily for the first 2 weeks, then 200 mg twice daily thereafter. Nevirapine induces it own metabolism via CYP3A4, and the dose increase 2 weeks into therapy is necessary to maintain adequate plasma drug levels. o No dose adjustment is needed for renal impairment short of dialysis, o and the use of nevirapine in the setting of hepatic dysfunction is not recommended. Nevirapine is a minor substrate for CYP2B6 and CYP2D6 and a weak inhibitor of CYP1A2, CYP2D6, and CYP3A4. o It is a major substrate and inducer of CYP3A4 and a strong inducer of CYP2B6. o As such, multiple clinically relevant drug-drug interactions are possible. o Antibiotics with antimycobacterial activity, such as rifampin, rifabutin, and clarithromycin, should not be co-administered with nevirapine. Inferior virologic outcomes were observed in HIV-infected patients receiving nevirapine-based antiretroviral therapy while on treatment for tuberculosis.65 Nevirapine decreases serum concentrations of some PIs and decreases plasma concentrations of oral contraceptives and methadone.66 A careful review of drug-drug interactions on a patient-by-patient basis is warranted prior to starting nevirapine. Nevirapine crosses the placenta and is known to enter breast milk.67-69 Nevirapine can be an effective component of a three-drug antiretroviral regimen.70,71 Nevirapine Nevirapine has lost favor relative to efavirenz for initial antiretroviral therapy, largely due to problematic toxicities that include o rash, o Stevens-Johnson syndrome, o and hepatic necrosis.72,73 An elevated risk of liver damage contraindicates the use of nevirapine in two subsets of patients: o women with CD4 counts greater than 250 cells/mm3 o and men with CD4 counts greater than 400 cells/mm3.74,75 Nevirapine can be used in pregnant women with CD4 counts less than 250cells/mm3 and has played a significant role in the prevention of mother-to-infant HIV transmission.76-78 o Single-dose nevirapine, however, is associated with alarming rates of NNRTI resistance in both mothers and infants, and combination therapies are now generally recommended in these situations.79-83 Resistance to nevirapine is conferred by any of the following mutations in RT: K103N, V106A/M, Y181C, Y188L, and G190A/S. o All of these NNRTI mutations reduce nevirapine sensitivity 50-fold or more.84,85 o The existence of any of these mutations in a patients HIV genotype precludes the effective use of nevirapine. Delavirdine is administered orally as 400 mg (two 200-mg pills) three times daily. In the modern era of consolidated and streamlined antiretroviral therapy, the pill burden and dosing schedule of delavirdine have made other NNRTI options preferable. Delavirdine As a result, delavirdine is now rarely used.18 Delavirdine is not recommended as initial therapy; very little clinical data exist to accurately guide its use.18

Efavirenz

Etravirine

Efavirenz is an NNRTI that is administered orally as a 600-mg tablet once daily, usually in the evening. Efavirenz is also available as a coformulation with tenofovir and emtricitabine. Efavirenz should be taken on an empty stomach; o a high-fat meal increases bioavailability and toxicity. No dose adjustment is needed in renal failure. Efavirenz o is a major substrate of CYP2B6 and CYP3A4; o a moderate inhibitor of CYP2C9, CYP2C19, and CYP3A4; o and an inducer of CYP2B6 and CYP3A4. Concomitant use with other drugs acting at CYP3A4 carries a high likelihood of drug-drug interactions. All PIs are substrates of CYP3A4 and drug-specific dose adjustments are necessary.86 There is no significant interaction between efavirenz and fluconazole, but an efavirenz dose adjustment is needed when co-administered with voriconazole. 87 Significant interactions can occur with antituberculosis therapies, particularly rifampin, although a large study demonstrated comparable virologic outcomes in patients receiving concomitant efavirenz-based therapy and antituberculosis treatment.65 Like nevirapine, efavirenz decreases plasma methadone levels and can precipitate acute withdrawal.88 Efavirenz is a preferred agent for use in initial antiretroviral regimens and demonstrates durable virologic suppression in combination regimens.24,39 Superior virologic outcomes have been seen when efavirenz-based therapy was compared with some PI-based (nelfinavir, indinavir, and lopinavir/ritonavir) or triple-NRTI-based regimens. 15,23,52,89,90 Comparable virologic outcomes were noted in a comparison to an atazanavir-containing regimen.91 As with other NNRTIs, efavirenz can cause rash and hepatotoxicity, although less commonly than nevirapine. o The two major toxicities of efavirenz are: central nervous system (CNS) adverse effects Adverse CNS effects include vivid dreams, insomnia, dizziness, and difficulty concentrating. Hallucinations, depression, and psychosis have been reported less commonly. o Efavirenz is often avoided in people with pre-existing psychiatric conditions. and teratogenicity. Efavirenz should not be used: o during pregnancy, o in women trying to conceive, o or in sexually active women not using contraception because of the risk of efavirenz-associated neural tube defects in newborns.92 Up to 50% of patients starting efavirenz can experience some CNS adverse effects, although these usually decrease over the first several weeks of therapy and can be partially ameliorated by evening dosing. Efavirenz resistance is most commonly conferred by the K103N substitution in RT, but all NNRTI mutations at positions 100, 106, 181, 188, 190, and 225 abrogate efavirenz activity.85 o Y181C is uncommonly selected during efavirenz therapy. The standard commercial genotypic assays cannot reliably detect resistance mutations present at less than 20% of the viral population.93 Consequently, some importance should also be placed on ascertaining the past NNRTI treatment history as a surrogate guide to the possible presence of key resistance mutations. Etravirine is a second-generation NNRTI that retains some activity in the presence of certain NNRTI resistance mutations. The drug acts as an allosteric inhibitor of HIV-1 reverse transcriptase. Etravirine is administered orally, 200 mg, as two 100-mg pills twice daily after a meal. o Ingestion without food decreases etravirine exposure by 50%. No dose adjustment is required for patients with renal insufficiency or mild to moderate hepatic insufficiency. As with other NNRTIs, etravirine has a relatively long half-life (41 20 hours). As a substrate and inducer of CYP3A4 and an inhibitor of other cytochromeP-450 isozymes, etravirine has important drug-drug interactions. o The drug cannot be co-administered with tipranavir,fosamprenavir, or atazanavir. o Etravirine should not be used with another NNRTI or any unboosted PI and should not be given with rifampin, clarithromycin, erythromycin, or anticonvulsants such as phenytoin or carbamazepine.

Rilpivirine

Etravirine has not been associated with fetal risk in animal studies, and there are no studies defining the risk of etravirine use in pregnant women. Two similar randomized, double-blind, placebo-controlled trials of etravirine and darunavir versus darunavir, both with optimized background therapy, demonstrated greater virologic suppression to less than 50 copies/mL after 24 weeks in subjects receiving etravirine and darunavir.94,95 Subjects in these trials had active or historical genotypic\evidence of NNRTI resistance-associated mutations. o However, a smaller randomized, phase IIb placebo-controlled trial of etravirine versus placebo, both with optimized background therapy did not demonstrate a significant reduction in viral loads in etravirine-treated subjects after 48 weeks; o in this study, subjects receiving etravirine had a median of one NNRTI resistance mutation at study entry.96 In PI-nave subjects with baseline NRTI and NNRTI resistance mutations, an etravirine-containing regimen was inferior to a regimen containing any PI, boosted or unboosted.97 Resistance to etravirine is associated with up to 17 different mutations in reverse transcriptase.98 o The most important resistance mutations appear to be Y181C and G190A and require the presence of other mutations to limit etravirine activity; K103N does not confer etravirine resistance. The most common adverse effects seen with etravirine are rash and nausea. o The rash, described as erythema or a papular eruption, usually begins in the second week of therapy and lasts for a median of 10 days.96 As with other NNRTIs, severe dermatologic reactions have been reported. [1][2] Rilpivirine (TMC278, brand name Edurant) is a pharmaceutical drug, developed by Tibotec, for the treatment of HIV infection. It is a second-generation non-nucleoside reverse transcriptase inhibitor(NNRTI) with higher potency, longer half-life and reduced side-effect profile compared with older NNRTIs, such [3][4] as efavirenz. [5][6] [7] Rilpivirine entered phase III clinical trials in April 2008, and was approved for use in the United States in May 2011. [8] A fixed-dose drug combining rilpivirine with emtricitabine and tenofovir, was approved by the U.S. Food and Drug Administration in August 2011 under the brand name Complera. Like etravirine, a second-generation NNRTI approved in 2008, rilpivirine is a diarylpyrimidine (DAPY).

3. Protease inhibitors (PIs) HIV relies on its aspartyl protease to cleave gag and gag-pol polyproteins into their essential structural and enzymatic (RT and integrase) components. Many human monomeric aspartyl proteases (e.g., renin and pepsin) exist, but it is the homodimer structure of HIV-1 and -2 protease that selectively binds to, and is inhibited by, PIs (Fig. 128-4, Table 128-3). Although viral particles can still be formed in the presence of PIs, they are rendered noninfectious. As a class, PIs are hepatically metabolized via the cytochrome P-450 isoenzyme CYP3A4. Ritonavir is a potent inhibitor of CYP3A4 metabolism; o this property has been exploited to beneficially increase, or boost, plasma drug levels of other PIs by co-administering subtherapeutic doses of ritonavir. o However, CYP3A4 inhibition can lead to drug-drug interactions with other medication classes that include: immunosuppresants, antiarrhythmics, antimycobacterials, other antiretroviral drugs, HMG-CoA reductase inhibitors (statins), methadone, and oral contraceptives. PIs can be effective components of initial, second-line, and salvage antiretroviral regimens, although dyslipidemias can be a problem with some agents and may develop within weeks to months of starting PI based therapy.99-102 Protease inhibitors have also been implicated in the development of insulin resistance.103-106 o Although certain PIs may increase the risk of insulin resistance and diabetes, this is unlikely to be a classwide effect and, in certain cases, may have more to do with a regimens NRTI backbone.107-113 Protease inhibitors often have a higher genetic barrier to resistance than either NNRTIs or integrase inhibitors and typically require multiple mutations to substantially lose antiviral activity, although exceptions exist (e.g., saquinavir and nelfinavir). o With most PIs, a major (or primary) mutation limits antiviral effectiveness and is followed by one or more minor (or secondary) mutations that by themselves do not dramatically affect phenotype but can improve viral fitness.85 Agents Description Saquinavir is administered as two 500-mg tablets (1000 mg) along with a ritonavir 100-mg tablet, both twice daily. The use of unboosted saquinavir is not recommended. Saquinavir bioavailability is improved with high-calorie, high-fat meals and should be taken within 2 hours of a full meal. The inhibition of CYP3A4 by saquinavir and ritonavir leads to drug-drug interactions. o For example, amiodarone, midazolam,lovastatin, simvastatin, and St. Johns wort should not be coadministered. o Concurrent use of rifampin is contraindicated because of hepatic toxicity, and levels of oral contraceptives are decreased. A complete review of a patients medications is warranted prior to the use of boosted saquinavir therapy. Early clinical experience with saquinavir was compromised by the poor bioavailability of a hard capsule formulation.14 o A soft gel formulation improved bioavailability and clinical outcomes but has since been replaced by the current 500-mg tablet.121,122 Saquinavir Twice-daily saquinavir/ritonavir (saquinavir/r) was compared to lopinavir/ritonavir(lopinavir/r), both in combination with tricitabine/tenofovir, andthey demonstrated similar virologic and immunologic outcomes.123 From the perspective of patient adherence, lopinavir/r retains a lower pill burden, can be taken without food, and can be stored above 34 C. A once-daily saquinavir/r dosing schedule has also been tested but demonstrated low drug trough concentrations; this dosing schedule is not currently recommended.124 Adverse effects of saquinavir/r are most commonly: o nausea, o vomiting, o diarrhea, o and abdominal discomfort. The major saquinavir resistance mutation is L90M within protease, although G48V can also be selected.

Ritonavir

Indinavir

Nelfinavir

Amprenavir & Fosamprenavir

Minor mutations can occur at positions 10, 24, 54, 62, 71, 73,77, 82, and 84. Ritonavir was originally marketed and used as a stand-alone protease inhibitor dosed at 600 mg orally twice daily. Gastrointestinal side effects, particularly diarrhea and nausea, were common and limited the drugs tolerability. o Dyslipidemias, vomiting, altered taste, and paresthesias were also reported. Today, ritonavir is usually used at lower doses (100 to 200 mg twice daily) to inhibit CYP3A4, improve the bioavailability, and increase the half-life of other PIs. o These low ritonavir doses decrease, but do not entirely eliminate, its gastrointestinal side effects. Ritonavir inhibits the metabolism of all available PIs but is not used in conjunction with nelfinavir. o Ritonavir boosting improves PI efficacy and decreases the occurrence of PI resistance after virologic failure, albeit at a cost of an increased incidence of clinically significant drug-drug interactions. o In several countries, all preferred PI-based treatment regimens include a recommendation for ritonavir boosting.18,26,36 When used at full dose, ritonavir selects for resistance mutations in a genotypic pattern similar to those selected for by indinavir.120 Indinavir is not recommended for initial antiretroviral therapy, boosted or unboosted, because of pill burden and the risk of nephro-lithiasis.125 o Unboosted indinavir is administered as two 400-mg capsulesevery 8 hours. o A boosted regimen combines two 400-mg indinavir capsules with one or two 100-mg ritonavir capsules twice daily. Indinavir must be taken with water, either 1 hour before or 2 hours after a meal. o Meal requirements do not apply to ritonavir-boosted indinavir (indinavir/r). Indinavir has low solubility at physiologic pH and cancrystallize in the kidney and urine.126,127 o Patients should increase their water intake to decrease the risk of nephrolithiasis associated with indinavir/r. CYP3A4 inhibition by indinavir can lead to multiple drug-drug interactions; o a thorough review of a patients medications is warranted prior to indinavir therapy. The main adverse effects seen with indinavir are: o nephrolithiasis, o unconjugated hyperbilirubinemia without jaundice, o abdominal pain, o nausea, o and dry skin and lips. Indinavi rhas been used in combination regimens with some success but has been largely replaced in recent years by less toxic and more tolerable PI regimens.128,129 The major indinavir resistance mutations selected during therapy are M46L, V82A, and I84V. o Minor mutations can occur at positions 10, 20, 24, 32, 36, 54, 71, 73, 76, 77, and 90. Nelfinavir is not generally recommended for initial antiviral therapy because of inferior viral efficacy relative to other PIs, notablyl opinavir/r, and the NNRTI efavirenz. Nelfinavir is administered ast wo 625-mg tablets (1250 mg total) twice daily with meals. It is primarily metabolized by CYP2C19 and CYP3A4 and is not boosted with ritonavir. Increasing doses of ritonavir did not necessarily increase the observed AUC of nelfinavir.130 The potential for drug-drug interactions is significant, as for other PIs, and a thorough review of a patients medications should be undertaken prior to nelfinavir therapy. Nelfinavir-induced viral suppression, when used in combination with two NRTIs, compares unfavourably with that induced by efavirenz, nevirapine, lopinavir/r, and fosamprenavir/r in antiretroviral-navepatients.15,131-134 Nelfinavir should not be used in PI-experienced patients.135 Adverse effects with nelfinavir include: o loose stools or diarrhea, o hypercholesterolemia, o and hypertriglyceridemia. The major nelfinavir resistance mutations are D30N and, less commonly, L90M. o Minor mutations can occur at amino acid positions 10, 36, 46, 71, 77,82, 84, and 88 within protease. Amprenavir is no longer available in the United States. o It has been replaced by fosamprenavir, the phosphorylated pro-drug of amprenavir, which improves oral bioavailability and efficacy. o Pill burden has also been improved but is still greater than with some other PIs.

Lopinavir + ritonavir

Once ingested, fosamprenavir is converted to amprenavir in the gut. Fosamprenaviris administered as a 700-mg tablet with a 100-mg ritonavir tablet, both twice daily; o a once-daily regimen of fosamprenavir 1400 mg with 100 to 200 mg ritonavir has also been used. o The twicedaily regimen is preferred; o Once-daily fosamprenavir/r should not be used in PI-experienced patients, and its use in treatment-nave patients cannot be recommended until efficacy is demonstrated in a sufficiently large randomized clinical trial. Fosamprenavir is metabolized byCYP3A4 and is excreted in feces. o The potential for drug-drug interactions is significant. No dose adjustment is required for renal insufficiency, but progressive dose reductions are needed in patients with worsening hepatic dysfunction. Early clinical experience with amprenavir demonstrates viral efficacy in combination regimens.136 o Patients receiving twice-daily fosamprenavir/r demonstrated similar viral load reductions and CD4cell count increases compared to those seen in nelfinavirtreatedpatients.134 o Less virologic failure was seen in fosamprenavir/r- treated patients than in those treated with nelfinavir. o A regimen containing twice-daily fosamprenavir/r demonstrated non-inferiority to alopinavir/r-containing regimen in the proportion of patients achieving plasma HIV RNA levels less than 50 copies/mL after 48 weeks oftherapy.111 o Similar increases in plasma lipid levels were seen with either therapy. Adverse effects of boosted fosamprenavir therapy include: o diarrhea, o hypertriglyceridemia, o and rash. Fosamprenavir contains a sulfonamide moiety that may explain the increased incidence of dermatologic side effects relative to other PIs. o Patients with a known sulfonamide allergy should be monitored when starting boosted fosamprenavir therapy. The major fosamprenavir resistance mutations are I50V and, less commonly,I84V.85 The valine substitution at position 50 selected by fosamprenavir is different than the leucine substitution selected at the same position by atazanavir (I50L); these mutations do not confer cross-resistance. o Minor mutations can occur at amino acid positions10, 32, 46, 47, 54, 73, 76, 82, and 90. Lopinavir is available only as a co-formulation with ritonavir. o It has been demonstrated that first-pass metabolism limits un boosted lopinavir plasma concentrations, whereas ritonavir boosting dramatically improves drug trough concentrations. The most recent formulation oflopinavir/ritonavir (lopinavir/r) is a heat-stable tablet that is administered as two lopinavir/r 200-mg/50-mg tablets twice daily. o This tablet can be taken without regard to food, although lopinavir/r solution should still be taken with meals. Lopinavir/r can also be given once a day, although not to pregnant women. Decreased clearance is not expected with renal insufficiency and some increase in lopinavir/r exposure occurs with worsening hepatic dysfunction. Significant CYP3A4 inhibition occurs, and a patients medications should be thoroughly reviewed prior to lopinavir/r therapy. Lopinavir/r has demonstrated efficacy in combination regimens in treatment-nave and -experienced patients, and it has frequently been used as the comparator PI in non-inferiority trials of new or newly formulated PIs.132,137 Lopinavir/r is superior to nelfinavir, whereas atazanavir/r, darunavir/r, fosamprenavir/r, and saquinavir/r have demonstrated non-inferior virologic outcomes compared to lopinavir/r in treatment-nave subjects.47,111,123,132,138,139 Virologic suppression on a lopinavir/r and 2NRTI regimen can be maintained for at least 7 years.140 A comparison of lopinavir/r or efavirenz, either with 2NRTIs, demonstrated superior virologic efficacy of an efavirenz-containing regimen but greater CD4 cell count gains with the lopinavir/r-containingregimen.23 Less drug resistance associated with virologic failure was seen in subjects randomized to lopinavir/r. Adverse effects seen with lopinavir/r are: o primarily gastrointestinal: diarrhea or loose stools, nausea, and, less commonly, vomiting. o Hypercholesterolemia

Atazanavir

Tipranavir

o and hypertriglyceridemia are reported in patients taking lopinavir/r. The major lopinavir/r resistance mutation is V82A, although V32I and I47A can also be selected. o Lopinavir/r resistance requires the accumulation of multiple mutations, often six or more, before the drug loses clinical effectiveness.141,142 o This is unlikely to occur in treatment-nave patients receiving lopinavir/r as part of recommended combination therapy. o Minor mutations have been documented at positions 10, 20, 24, 33, 46, 50 (I50V), 53, 54, 63, 71, 73, 76,84, and 90. o When mutations V32I and I47A are found together with mutations at position 46, they are associated with high-level lopinavir/r resistance.143,144 Atazanavir can be administered either as o a 400-mg capsule once daily in treatment-nave patients o or preferably as a 300-mg capsule combined with 100 mg ritonavir, o both once daily, for treatment-nave and treatment-experienced patients. Both boosted and unboosted atazanavir should be taken with food. No dose adjustment is needed for renal dysfunction in treatment-nave patients, o but a recommendation exists not to use atazanavir in treatment-experienced dialysis patients. Moderate hepatic impairment necessitates a dose reduction to atazanavir, 300 mg once daily, and the drug should not be used in severe (Child-Pugh class C) hepatic insufficiency. Atazanavir is metabolized by CYP3A4 and can also affect CYP2C8 and UGT1A1 substrates. o Methadone steady-state levels appear unaffected by atazanavir.145 The absorption of atazanavir requires a low gastric pH; o interactions with antacids and H2 antagonists are possible. Atazanavir and proton pump inhibitors should not be co-administered in treatment-experienced patients.146 Nevirapine should not be co-administered with either boosted or unboosted atazanavir. Unboosted atazanavir has shown comparable efficacy to nelfinavir and efavirenz in treatment-nave subjects.91,147,148 The recommendation for ritonavir boosting of atazanavir in treatment-nave patients is derived from two studies o one that directly compared boosted and unboosted atazanavir over 96 weeks o and one that compared atazanavir/r to lopinavir/r over 48 weeks.47,149 o Similar virologic response rates were seen with unboosted and boosted atazanavir, although there were more treatment failures and atazanavir resistance in participants receiving an unboosted atazanavir-containing regimen. o Atazanavir/r demonstrated non-inferiority to lopinavir/r over 48 weeks of therapy. o There were fewer dyslipidemias and diarrhea in participants receiving atazanavir/r, although this trial used an older lopinavir/r formulation that is no longer available. In an unrelated trial, the combination of atazanavir/didanosine/emtricitabine was associated with inferior virologic outcomes compared to either zidovudine/lamivudine/efavirenzor tenofovir/emtricitabine/efavirenz; o the combination of atazanavir/didanosine/emtricitabine should not be used.150 Adverse effects associated with atazanavir include: o nausea, o hyperbilirubinemia with jaundice and scleral icterus, o rash, o and nephrolithiasis.151,152 o Atazanavir has less effect on serum cholesterol and triglycerides than do other PIs. o Ritonavir boosting of atazanavir comes at a cost of more hyperbilirubinemia and a greater adverse effect on serum lipid profiles. The primary atazanavir resistance mutation is the I50L substitution; I84V also significantly limits drug activity. o Minor mutations occur at positions 10, 16, 20, 24, 32, 33, 34, 36, 46, 48, 53, 54, 60, 62, 64, 71, 73, 82, 85, 90, and 93. o In general, the presence of three or more of these mutations predicts a loss of virologic response to atazanavir.153 For the practicing clinician, the simplest approach may be to order a resistance phenotype that will integrate all the aforementioned genotypic information in a more concise and straightforward manner. Tipranavir is a non-peptidic PI approved for use in treatment-experienced patients with resistance to multiple other PIs. The drug is administered at 500 mg twice daily with ritonavir 200 mg twice daily and should be taken with a high-fat meal. No dose adjustments are required for patients with renal or mild hepatic impairment; o Tipranavir is contraindicated in patients with moderate to severe liver dysfunction.

Darunavir

Tipranavir capsules are thermally labile and must be kept below77 F. Complex drug-drug interactions occur as a result of the net effect of tipranavir and ritonavir inducing P-glycoprotein and inhibiting CYP3A4. o As a consequence, tipranavir cannot be co-administered with rifampin, several antiarrhythmics, lopinavir, saquinavir, and amprenavir. o Numerous other tipranavir interactions exist, including increases in rifabutin levels o and significant reductions in the levels of co-administered methadone and oral contraceptives. Tipranavir has been shown to induce adverse fetal effects in animal studies; no studies assessing risk in pregnant women have been performed. The efficacy of tipranavir in treatment-experienced subjects with PI-resistant virus was demonstrated in two randomized trials,RESIST-1 and -2.154 o Subjects enrolled in these trials were required to have at least one primary PI resistance mutation but could not have more than three at codons 33, 82, 84, or 90. o After 48 weeks, more subjects randomized to tipranavir/ritonavir plus optimized background therapy achieved viral loads less than 50 copies/mL than subjects receiving a ritonavir-boosted comparator PI (23% versus 10%).154 Tipranavir/ritonavir has also shown sustained virologic responses in pediatric and adolescent patients.155 Tipranavir has been associated with severe hepatotoxicity and intracranial hemorrhage. o Thirteen of 6840 patients receiving tipranavir in clinical trials developed intracranial hemorrhages, and for this reason patients at risk for bleeding from trauma, surgery, or other medical conditions (e.g., hemophilia), or who are taking other drugs thatincrease the risk for bleeding, should not receive tipranavir. The most common adverse effects seen with tipranavir are nausea and diarrhea, o in part due to the increased dosage of ritonavir required for boosting. Tipranavir contains a sulfonamide moiety; o the proportion of patients with a sulfonamide allergy that react unfavorably to tipranavir is unknown. Darunavir is a PI with activity against some PI-resistant viruses. Its efficacy was first validated when boosted with ritonavir in treatment-experienced patients. o On the basis of additional trials, ritonavir-boosted darunavir can now also be considered as a first-line PI in patients initiating antiretroviral therapy. No dose adjustments are needed for patients with mild/moderate renal insufficiency or mild/moderate hepatic impairment. o No data are available on dosing in severe renal failure; o the use of darunavir in patients with severe hepatic impairment is not recommended. In treatment-experienced patients, o darunavir is administered with meals as a 600-mg tablet twice daily with ritonavir (100 mg). In treatment-nave patients, o arunavir/ritonavir has been studied at an800-mg/100-mg once-daily dose. The drug contains a sulfa moiety and should be used with caution in patients with sulfonamide allergies. Darunavir can be used in conjunction with atazanavir, efavirenz, andetravirine. o It is not recommended for use, however, with: lopinavir/ritonavir, saquinavir, lovastatin, or simvastatin. Two randomized phase IIb studies (POWER-1 and -2) in treatment-experienced patients with, on average, three primary PI resistance mutations and an 80-fold or greater baseline change in lopinavir susceptibility demonstrated greater viral load reductions and CD4 lymphocyte increases after 24 weeks of therapy in patients receiving darunavir/ritonavir compared to an investigator-selected PI, both witho ptimized background therapy.156 o At 48 weeks, a greater proportion ofdarunavir/ritonavir-treated than comparator-PI-treated subjects had plasma HIV-1 RNA less than 50 copies/mL (45% versus 10%). In a separate trial comparing darunavir/ritonavir to lopinavir/ritonavir: o in lopinavir-nave, treatment-experienced patients: darunavir/ritonavir was noninferior to lopinavir/ritonavir in achieving plasma HIV-1 RNA less than 400 copies/mL at

48 weeks.157 In treatment-nave patients, darunavir/ritonavir was non-inferior to lopinavir/ritonavir after 48weeks of treatment in achieving HIV-1 RNA less than 50 copies/mL.139 The dose of darunavir/ritonavir studied in treatment-nave subjects was 800 mg/100 mg once daily, rather than the 600-mg/100-mg twice daily dose previously studied in treatment-experienced subjects. Adverse effects seen with darunavir include: o diarrhea, o nausea, o headache, o and nasopharyngitis; o 0.5% of subjects enrolled in clinical trials of ritonavir-boosted darunavir developed acute hepatitis. o Post marketing cases of liver injury and death have been reported. Genotypic data from the screening samples of the POWER studies suggest that several darunavir-associated resistance mutations exist. o The I50V mutation, one that is also selected by amprenavir, confers the greatest resistance with a more than fourfold change increase o However, a single darunavir resistance-associated mutation, evenI50V, does not confer resistance; two or more mutations are required. o Mutations V11I, I54L, G73S, and L89V confer the least resistance, with each contributing a less than twofold increase in resistance. o Mutations V32I, L33F, I47V, I54M, L76V, and I84V lead to an intermediate two to fourfold increase. Treatment-experienced patients should preferably not start darunavir (or tipranavir) without first obtaining a virus resistance phenotype. o This is because the limited clinical experience with these PIs may initially compromise the accuracy of the genotypic algorithms used to predict drug sensitivity. o

4. Fusion inhibitors HIV entry shares common mechanisms with several other enveloped viruses.158 The HIV-1 surface glycoproteins gp120 and gp41 mediate viral binding to and membrane fusion with host target cells (Fig. 128- 5). o The env gene product is first translated as gp160 and then cleaved intracellularly into gp120 and gp41. Both gp120 and gp41 traffic to the viral membrane and are the only two proteins known to extrude from its surface. o On the viral membrane, there is a noncovalent association of one molecule of gp120 with one molecule of gp41.159 o Three of these units aggregate on the membrane surface to form the gp120/gp41 heterotrimer.160-162 o The association of gp120 with gp41 in the trimer traps gp41 in a conformationally metastable state, the energy from which can later be exploited to accelerate the rate of fusion.163 Binding of gp120 to its primary receptor, CD4, is the first step leading to membrane fusion. o After CD4 binding, binding of coreceptor occurs, although some interactions of CD4 with gp120 lead to shedding of gp120 and inactivation of the fusion reaction.164 o If gp120 is not shed, fusion requires the binding of either CCR5 or CXCR4 to proceed.165-169 o The interaction of gp120 with CD4 forms the co-receptor binding site.170 o Co-receptor recognition is defined by structural elements of gp120 that include the V1-V2 region, the bridging sheet (an antiparallel, four-stranded sheet that connects the inner and outer domains of gp120), and, most important, the V3 loop.170-173 o According to current models of HIV-1 entry, sequential binding of gp120 to CD4 and co-receptor leads to the release of gp41 from its metastable conformation. o The hydrophobic N-terminal fusion domain of gp41, now free, inserts into the target membrane.163,174,175 o Two trimeric coiled coil structures in gp41, termed heptad repeat 1 (HR1) and heptad repeat 2 (HR2), rearrange to form a six-helix bundle that leads to the approximation of the two membranes, receptor-mediated internalization of virus (endocytosis), and eventual fusion.158,158a Enfuvirtide is a peptide mimetic of gp41 HR2 that interferes with the HR1-HR2 association, whereas maraviroc binds to CCR5, changes its conformation, and prevents gp120-CCR5 binding (Table 1284).176 Agent Description Enfuvirtide is a 36-amino acid synthetic peptide that is administered as a 90-mg subcutaneous injection twice daily; o the location of the injection does not affect bioavailability. o No dose adjustment is required for hepatic or renal impairment. o No clinically significant drug interactions with enfuvirtide have been reported. Studies in animals demonstrated no teratogenic effects of enfuvirtide, and there are no formal studies in pregnant women to assess fetal risk from enfuvirtide use. o Two similar randomized, open-label trials in approximately 1000 treatment-experienced subjects with advanced HIV disease (medianCD4 count,