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Table 2.1: Antiretroviral agents Trade name Abbrev. Drug Manufacturer Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs) Combivir™ CBV AZT+3TC GSK Emtriva™ FTC Emtricitabine Gilead Epivir™ 3TC Lamivudine GSK HIVID™* ddC Zalcitabine Roche Kivexa/Epzicom™ KVX 3TC+ABC GSK Retrovir™ AZT Zidovudine GSK Trizivir™ TZV AZT+3TC+ABC GSK Truvada™ TVD FTC+TDF Gilead Videx™ ddI Didanosine BMS Viread™ TDF Tenofovir Gilead Zerit™ d4T Stavudine BMS Ziagen™ ABC Abacavir GSK Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Rescriptor™ DLV Delavirdine Pfizer Sustiva/Stocrin™ EFV Efavirenz BMS/MSD Viramune™ NVP Nevirapine Boehringer Ingelheim Protease Inhibitors (PIs) Aptivus™ TPV Tipranavir Boehringer-Ingelheim Agenerase™ APV Amprenavir GSK Crixivan™ IDV Indinavir MSD Invirase 500™ SQV Saquinavir Roche Kaletra™ LPV Lopinavir/ritonavir Abbott Norvir™ RTV Ritonavir Abbott Reyataz™ ATV Atazanavir BMS Telzir/Lexiva™ FPV Fosamprenavir GSK Viracept™ NFV Nelfinavir Roche/Pfizer Fusion inhibitors Fuzeon T-20 Enfuvirtide Roche Entry inhibitors Celsentri/Selzentry™ MVC Maraviroc Pfizer *Distribution ceased Currently, 25 single or combination preparations from four classes of drugs are licensed: nucleoside and nucleotide analogs (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs) and fusion inhibitors. Further drugs and new classes of drugs can be expected in the next few years. The following chapter provides an overview of the individual agents and their specific features and problems. Common combinations are described in the chapter on "Which HAART to Start With". Nucleoside analogs (NRTIs) Mechanism of action Nucleoside analogs ("nukes") are also referred to as nucleoside reverse transcriptase inhibitors. Their target is the HIV enzyme reverse transcriptase. Acting as alternative substrates or "false building bricks", they compete with physiological nucleosides, differing from them only by a minor modification in the ribose molecule. The incorporation of nucleoside analogs induces the abortion of DNA synthesis, as phosphodiester bridges can no longer be built to stabilize the double strand. Nucleoside analogs are "prodrugs", which means that they are absorbed unchanged and only activated when three phosphates are attached by intracellular phosphorylation in a stepwise process. It is the triphosphate derivative that is efficacious. AZT and d4T are thymidine analogs, while FTC and 3TC are cytidine analogs. Combinations containing AZT + d4T or FTC + 3TC are therefore pointless, since both drugs compete for the same bases (Havlir 2002). ddI is an inosine analog, which is converted to dideoxyadenosine; abacavir is a guanosine analog. There is a high degree of cross-resistance between nucleoside analogs (see also "Resistance"). Nucleoside analogs were the first drugs to be used in HIV treatment, and therefore, most of the experience is based on them. They are easy to take, and once-daily dosing is sufficient for most. Overall initial tolerability is fairly good. However, frequent complaints during the first weeks are fatigue, headache and gastrointestinal problems, which range from mild abdominal discomfort to nausea, vomiting and diarrhea. The gastrointestinal complaints are easily treated symptomatically (see "Side Effects"). However, nucleoside analogs can cause a wide variety of long-term side effects, including myelotoxicity, lactate acidosis, polyneuropathy and pancreatitis. Although lipodystrophy was initially linked exclusively to treatment with PIs, many metabolic disorders, and especially lipoatrophy, are now also attributed to nucleoside analogs (Galli 2002). They are probably related to mitochondrial toxicity, which was first described in 1999 (Brinkmann 1999). Mitochondrial function requires nucleosides. The metabolism of these important organelles is disrupted by the incorporation of false nucleosides, leading to mitochondrial degeneration. There are probably considerable differences between the individual drugs with regard to mitochondrial toxicity (for further details see "Mitochondrial toxicity"). Nucleoside analogs are eliminated mainly by renal excretion and do not interact with drugs that are metabolized by hepatic enzymes. There is therefore little potential for interaction. However, ribavirin, for example, can also reduce intracellular phosphorylation of AZT or d4T (Piscitelli 2001). In contrast to the PIs and NNRTIs, the doses have to be adjusted for patients with renal insufficiency. Individual agents Abacavir (Ziagen™) is a guanosine analog, which can lower viral load by approximately 1.4 logs within 4 weeks (Harrigan 2000). Abacavir is phosphorylated intracellularly to carbovir triphosphate, which has a long half-life (Harris 2002). In October 2004, following larger studies, abacavir was licensed for once-daily therapy (Moyle 2005, Sosa 2005). It is also a component of Trizivir™ and Kivexa™. In combination with AZT+3TC (Trizivir™, see also Triple Nuke), abacavir was less effective than efavirenz (Gulick 2004). The randomized, double blind CNA3005 Study also showed lower efficacy in comparison to indinavir, particularly with higher viral load (Staszewski 2001). In contrast, efficacy was comparable to that of nelfinavir (Matheron 2003). When combined with 3TC, the efficacy is similar to that of 3TC plus either AZT (DeJesus 2004) or d4T (Podzamczer 2006). A regimen that is failing virologically can be successfully intensified with abacavir if it is added early enough, and if the viral load is not too high (Katlama 2000, Rozenbaum 2001). Abacavir is also used to simplify HAART. Numerous randomized studies have demonstrated that patients on a successful PI- or NNRTI-regimen can switch relatively safely to abacavir plus two NRTIs (Clumeck 2001, Katlama 2003, Martinez 2003, Bonjoch 2005). However, there is a certain degree of risk associated with this, and particularly in extensively pretreated patients, virological failure is possible (Opravil 2002, Martinez 2003). Caution therefore must be taken when combining tenofovir with 3TC as resistance mutations can rapidly develop (see section on "Triple Nuke"). With respect to mitochondrial toxicity, abacavir is more favorable than several other substances. In comparison to d4T, the lipoatrophy risk is low (Podczamcer 2006). Lipoatrophy improves on changing from d4T to abacavir (Carr 2002, John 2003, Moyle 2003, McComsey 2004). This also applies to an increase in mitochondrial DNA (Hoy 2004, Martin 2004, McComsey 2005). One drawback to the use of abacavir is the risk of a hypersensitivity reaction (HSR), an allergic reaction that is associated with fever and lethargy (see chapter on Side Effects). This occurs in 4-6 % of patients, almost always within the first six weeks of treatment. In acutely infected patients, the risk seems to be higher (up to 18 %), and abacavir should be avoided (Stekler 2006). On re-exposure, HSR can even be fatal. Severe HSR can occur after only a single abacavir tablet (De la Rosa 2004) or even after treatment interruption despite prior tolerability (El-Sahly 2004). The combination of strongly worded warnings contained in the package insert and the unspecific symptoms of HSR poses a constant challenge to the physician. A genetic predisposition exists, so that patients with HLA type B5701 are at a higher risk than others - with HSR occurring in up to 80 % of them (Mallal 2002, Hetherington 2002). However, HSR is also possible in the absence of this HLA type. Data from the PREDICT study, in which the predictive value of the HLA type was prospectively investigated in approximately 2,000 patients, is being eagerly awaited. In the future, it may be possible to assess HLA type before administration of abacavir, a strategy already practiced in some countries. AZT (Zidovudine, Retrovir™) was the first antiretroviral agent to be put on the market, in 1987. An initial study on AZT monotherapy showed a survival benefit - at least in significantly immunocompromised patients (Fischl 1987). In contrast, two other early, very large studies, ACTG 016 and 019, demonstrated no significant survival benefit in asymptomatic patients, although the risk for progression was significantly reduced in both (Fischl 1990, Volberding 1990). Even at that time, it started to become apparent that the success of AZT monotherapy was likely to be limited. The Concorde Study has even brought AZT from time to time into disrepute: it showed that there was no long-term benefit of AZT treatment. In addition, the higher doses that were given in these first few years led to considerable myelotoxicity (Fischl 1990a), something which should also not be underestimated for the standard current doses - check the blood count! Long-term treatment almost always increases MCV (mean corpuscular volume of erythrocytes), which is useful as a means of assessing adherence. Gastrointestinal complaints, especially initially, may present a further problem. In contrast, AZT-related myopathy or even cardiomyopathy is quite rare. A "logical" disadvantage of AZT is that it has to be taken twice daily, disqualifying it as a substance for once-daily combinations. Furthermore, AZT finally came under pressure when, in the 934 study, it scored significantly worse than tenofovir, mainly due to poorer tolerability. Severe anemia was significantly increased in the AZT-arm in comparison to tenofovir, causing 5.5 % of cases to drop out (Gallant 2006). Lack of neurotoxicity and good CNS penetration are some of the advantages of this drug. Therefore, AZT still remains a component of many regimens and transmission prophylaxes. AZT is also a component of both Combivir™ and Trizivir™, at a slightly higher dose (300 instead of 250 mg), which may occasionally lead to higher myelotoxicity. It is noteworthy that the US-patent protection of AZT expired in 2005, so that AZT could soon become much cheaper. ddC - Zalcitabine (HIVID™) was, in 1992, the third NRTI to reach the market. The weak efficacy as well as problems with the pharmacokinetics and side effects resulted in ddC being taken from the market in 2006 - a first for HIV medicine. ddI - (Didanosine, Videx™) in 1991, was the second nucleoside analog to be licensed. The introduction of acid-resistant tablets, which, in 2000, replaced the chewable tablets, improved tolerability and patient acceptance significantly. Early studies showed a survival advantage for treatment-naïve patients with AZT+ddI compared to AZT monotherapy. This effect of ddI was less marked in AZT-pretreated patients. Therefore, the addition of ddI in the Delta 2 study led to significant survival benefit, although this was not the case in CPCRA007 (Saravolatz 1996). In ACTG 175, monotherapy with ddI was more potent than AZT, even with regard to disease progression (Hammer 1996). However, this predominance was not confirmed in other studies (Dolin 1995, Floridia 1997). Following failure of AZT, ddI is much more effective than d4T (Havlir 2000). In more recent studies, ddI is only used seldomly. Gastrointestinal complaints and polyneuropathy are the main side effects. Pancreatitis is more specific, occurring in up to 10 %, and can be fatal in individual cases. This toxicity is probably dose-dependent (Jablonowski 1995). This is possibly related to disorders of purine metabolism (Moyle 2004). Special caution should be given to combinations with ribavirin, hydroxyurea or tenofovir (Havlir 2001, Martinez 2004). Concomitant administration of these drugs should be avoided. Even the combination with d4T, is no longer recommended, especially in primary therapy (see especially the chapter on "Problematic primary therapy"). Patients with a history of pancreatitis should not be treated with ddI. If the body weight is less than 60 kg, the dose should be reduced from 400 mg to 250 mg. ddI has to be administered on an empty stomach. In view of its toxicity ddI has become less popular but is useful in certain resistance situations (Molina 2005). d4T (Stavudine, Zerit™) was the second thymidine analog to be introduced after AZT. Subjectively, d4T is often initially tolerated better than AZT (less gastrointestinal side effects and limited myelotoxicity), is certainly just as effective (Spruance 1997, Squires 2000), and used to be one of the most frequently prescribed HIV drugs. However, several studies have since placed it under a lot of pressure. In the Gilead 903 Study, d4T was tested in a double blind design against tenofovir in treatment-naïve patients. Both drugs showed comparable efficacy, but d4T had considerable mitochondrial toxicity (Gallant 2004). In fact, the FTC-301 Study, in which d4T was tested in a double blind design against FTC had to be prematurely terminated, because d4T was not only more toxic, but also weaker (Saag 2004). It is now beyond doubt that long-term toxicity occurs more frequently with d4T than with other NRTIs. The data is depressing: not only from the laboratory (Martin 2004, McComsey 2005), but also from clinical observations. d4T is a risk factor for lactic acidosis, hyperlactacidemia and Guillain-Barré-like syndromes (Mokrzycki 2000, John 2001, Shah 2003). In cohort studies, the risk of lipoatrophy on d4T doubled in one year (Mauss 2002); it tripled in two years (Bernasconi 2002). Other studies point in the same direction (Mallal 2000, Chene 2002, Mallon 2003, Podcamzer 2006). Furthermore, numerous studies have now been published in which substitution of d4T with other NRTIs, particularly abacavir or tenofovir, had positive effects on lipoatrophy and other metabolic disorders (Carr 2002, John 2003, Moyle 2003, Martin 2004, McComsey 2004, Libre 2006). Based on current data, d4T should be avoided wherever possible and replaced, ideally with abacavir or tenofovir if the resistance profile permits (Moyle 2006). In the so-called developing countries, the situation is different, and it remains an important combination partner, particularly due to the lack of myelotoxicity. 3TC (Lamivudine, Epivir™) was, in August 1996, the fifth NRTI to be licensed in Europe. It is a well-tolerated cytidine analog, whose substantial disadvantage is rapid development of resistance. A single point mutation (M184V) is sufficient to cause loss of efficacy. On monotherapy, this mutation is likely to lead to resistance after only a few weeks (Eron 1995). The full effect of 3TC only emerges in combination with other NRTIs. As a component of Combivir™, Kivexa™ and Trizivir™, 3TC is actually one of the most frequently used antiretroviral agents of all. In studies such as NUCB 3002 or CAESAR, 3TC significantly improved disease progression and survival when added to NRTI therapy (Staszewski 1997). However, the M184V point mutation can increase susceptibility of certain AZT-resistant viruses and also impair viral fitness (Miller 2002). The continuation of 3TC-monotherapy in treatment-experienced patients with the M184V mutation was associated with a smaller increase in the viral load and drop in CD4 cell count than the complete interruption of HAART (see also "Salvage Therapy"). Keeping 3TC as part of the therapy despite proven resistance is therefore sensible to conserve the M184V mutation and thus reduce the replicative capacity of HIV. In the Atlantic Study, 3TC in combination with d4T+ddI proved weaker virologically than indinavir or nevirapine (Van Leeuwen 2003). Combination with abacavir and tenofovir is now not recommended as a triple nucleoside regimen (see the section "Triple Nuke"). The antiviral potency is approximately comparable to that of the "main competitor" FTC (Rousseau 2003, Benson 2004). Although the half-life is not as long as for FTC, 3TC is also licensed for once-daily dosing (DeJesus 2004). An important effect of 3TC is also its relatively good efficacy against hepatitis B viruses, although this is again limited by the relatively rapid development of resistance. FTC (Emtricitabine, Emtriva™) is a cytidine analog, which is biochemically very similar to 3TC, but has a longer half-life. Once-daily dosing is possible. Like 3TC, it has HBV efficacy, tolerability is good, and it has a narrow interaction potential (Framptom 2005). FTC seems to have a low affinity for the mitochondrial polymerase, so the risk of mitochondrial toxicity is likely to be relatively low. In monotherapy studies as well as in combination with AZT, FTC was at least as effective as 3TC (Rousseau 2003, Benson 2004). However, as with 3TC, efficacy is limited by the M184V point mutation. Subsequent to data from the FTC-301 Study (Saag 2004), the drug was licensed in 2003. This randomized, double blind trial showed that FTC was clearly more effective and tolerable than d4T (Gallant 2006), although this was probably not due to differences between FTC and 3TC. The ALIZE study demonstrated the good long-term tolerability and efficacy of a once-daily combination of FTC+ddI+efavirenz (Molina 2005). Today, FTC is an important combination partner in HAART, particularly in the fixed-dose combination with tenofovir (Truvada™). In contrast, FTC alone only has a minor role to play. TDF (Tenofovir, Viread™) acts as a false building block similar to nucleoside analogs, targeting the enzyme reverse transcriptase. However, in addition to the pentose and nucleic base, it is monophosphorylated and therefore referred to as a nucleotide analog. The accurate description of the substance is tenofovir DF (tenofovir disoproxil fumarate = TDF), referring to the phosphonate form from which the phosphonate component is only removed by a serum esterase, and which is activated intracellularly in two phosphorylation steps (Robbins 1998). In the 902 and 907 studies, in which tenofovir was added to existing HAART, the viral load fell by approximately 0.6 logs after 48 weeks (Schooley 2002, Squires 2003). Tenofovir is tolerated very well: side effects were as low as in the placebo arm. In the 903 Study, in which tenofovir was tested against d4T in treatment-naïve patients, results showed at least equivalent potency (Gallant 2004). However, the incidences of polyneuropathy and dyslipidemias were significantly reduced. Analogous to this are the in vitro data, which show that phosphorylated tenofovir only has a low affinity for mitochondrial polymerases (Suo 1998). As a result of this convincing clinical data and its licensing in 2001, the drug is now very widely used. Furthermore, in the 934 study, TDF+FTC was significantly better than AZT+3TC (Gallant 2006), particularly due to the improved tolerability. Tenofovir can also help to improve d4T-induced lipoatrophy and dyslipidemias (Moyle 2006, Llibre 2006). However, the extensive use has revealed a few problems. In particular, the combination of ddI should be avoided for diverse reasons (see "Problematic Primary Therapy"). An unfavorable interaction occurs with atazanavir, which means atazanavir has to be boosted (Taburet 2004). Reduced efficacy occur with particular triple nuke combinations(see corresponding section). In the case of virological treatment failure on tenofovir, the K65R mutation, a problematic nucleoside analog resistance, is frequently found. However, the potential risk of nephrotoxicity is a serious problem for tenofovir (see the chapter "HHIV and Kidneys"), which is associated with a mild to moderate disturbance of renal function (Gallant 2005, Mauss 2005, Thompson 2006, Heffelfinger 2006). Severe disturbances are rare. In the Swiss cohort, 46 out of 2,592 patients (1.6 %) had to stop tenofovir because of renal toxicity, after on average 442 days (Fux 2007). Renal failure on tenofovir can also be observed in the context of a Fanconi syndrome, a defect of proximal tubular transport (Karras 2003, Schaaf 2003, Peyriere 2004). Patients with renal disease should either not be treated with tenofovir, or at least receive a lower dose (see "Drugs"). Elderly and lighter patients are particularly at risk (Crane 2006), although it is not possible to predict patients at risk. According to the current data, it is important to remain alert and to regularly check renal function on therapy. The choice of NRTI backbones Until now, all classical HAART regimens have always contained two nucleoside analogs or nucleotide analogs as the "backbone" ("nuke backbone"). As knowledge has grown about the mitochondrial toxicity of some nucleoside analogs, this concept is now being questioned by an increasing number of experts. However, data on combinations that are completely without NRTIs (see "Nuke Sparing") are still relatively sparse, so that there are currently no recommendations for such strategies. Earlier NRTI backbones usually contained a thymidine analog (TA), in the form of AZT or d4T. However, because of the toxicity problems of both substances, as well as the problematic resistances associated with failure of therapy (see "Resistance"), it is usually changed to a TA-free backbone. The most important are TDF+3TC, TDF+FTC and ABC+3TC. These combinations have the advantage that they can be administered once daily: TDF+FTC and ABC+3TC can even be taken in a single tablet. Therefore, they have replaced the long-standing backbone of AZT+3TC. TDF+3TC/FTC Good data is available for tenofovir-based therapy (Molina 2004), especially in combination with efavirenz. In the Gilead 903 Study, the combination of TDF+3TC was not only as virologically effective as d4T+3TC, but was also tolerated much better (Gallant 2004). Since the introduction of FTC and the combined tablet Truvada™ in August 2004, tenofovir has been administered more frequently together with FTC than with 3TC. TDF+FTC is currently the most commonly used backbone in Phase III/IV studies. In the Gilead 934 Study (Gallant 2006), using 509 treatment-naïve patients, TDF+FTC was compared to AZT+3TC (both with efavirenz). At 48 weeks, more patients on TDF+FTC reached a viral load of less than 50 copies/ml (80 versus 70 %). The significant differences were primarily related to the poorer tolerability of AZT+3TC, which often resulted in the discontinuation of therapy (9 versus 4 %). Virological failure and resistance mutations were approximately equal in both arms and were infrequent. At 96 weeks, no further significant differences were observed, although lipoatrophy side effects were rarer with TDF+FTC than with AZT+3TC (Pozniak 2006). In the future, tenofovir therapy will play an important role - providing no undesirable surprises arise with regard to nephrotoxicity. ABC+3TC A real alternative to AZT+3TC is ABC+3TC, which is available in a fixed combination as Kivexa™ or Epzicom™. The double blind randomized CNA30024 Study showed the non-inferiority of ABC+3TC in comparison to Combivir™ (DeJesus 2004). It even led to a significantly higher rise in CD4 cells, although there was a higher rate of allergies at 9 versus 3 % (DeJesus 2004). The ZODIAC study also demonstrated good potency for ABC+3TC and efavirenz (Moyle 2004). In the ABCDE study, ABC+3TC had the same efficacy as d4T+3TC, but was also less toxic (Podzamczer 2006). So far, there are no comparable studies on TDF+FTC. It is important to note that ABC+3TC has a significantly shorter half-life. Whether this could result in less "forgiveness" for irregular dosing and the development of resistances, is still not clear. In comparison to TDF+FTC there could be an advantage in that L74V, usually occurring alongside the M184V mutation, is associated with less cross-resistance than the tenofovir-associated K65R mutation. However, a significant disadvantage of the combination with NNRTIs is the higher risk of occurrence of allergies under both abacavir and NNRTIs, making it difficult to distinguish between a NNRTI rash and the abacavir HSR. We therefore do not recommend using these at the same time, as treatment options may be unnecessarily eliminated. It should be noted that most of the studies cited here were investigating first-line therapy. In treatment-experienced patients, numerous other individually tailored backbones may become necessary as a result of resistance and intolerability. However, the combinations discussed below should be avoided if possible. AZT+3TC In many guidelines, AZT+3TC is still regarded as the standard backbone for first-line therapy. There is more experience with this combination than with any other. The resistance profile is favorable: the M184V mutation that frequently develops during 3TC treatment probably increases sensitivity to AZT. AZT+3TC is usually given as Combivir™. Although the licensing study for Combivir™ showed no differences in toxicity (Eron 2000), in our experience the 300 mg AZT dose in Combivir™ is too high for some patients (e.g. pregnant women) and can lead to anemia. In such cases, it is worth trying AZT+3TC as individual formulations, so that the dose of AZT can be reduced to 250 mg. AZT+3TC has comparable efficacy to d4T+3TC (Foudraine 1998, Eron 2000, Squires 2000), or AZT+FTC, which were frequently used earlier (Benson 2004). The ACTG 384 study showed superiority of AZT+3TC over d4T+ddI (Robbins 2003, Shafer 2003), which underpinned its status as a standard therapy. In the last few years, this has started to crumble: the initially lower rate of lipoatrophy (Molina 1999) actually just occurs later than with d4T+ddI. Furthermore, AZT+3TC were shown by the Gilead 934 Study to be less effective (tolerated less) than TDF+FTC (Gallant 2006, Pozniak 2006). In contrast to ABC+3TC, immune reconstitution appears to be worse (DeJesus 2004). Poor and non-recommended backbones Almost all guidelines now explicitly recommend avoiding the previously popular d4T+ddI combination. Mitochondrial toxicity is too high, and it is inferior to AZT+3TC (Robbins 2003). In cases of treatment failure, thymidine analog mutations (TAMs) are usually present, which can limit future options. In view of the wide selection of NRTIs available today, ddI+d4T is no longer justified at least for first-line therapy. d4T+3TC is another combination recommended only in certain situations for first-line therapy. Although it is subjectively very well tolerated initially, d4T leads to problems with long-term toxicity. Studies such as ABCDE or 903 have shown that d4T+3TC cause more lipoatrophy than ABC+3TC or TDF+3TC (Gallant 2004, Podzamczer 2006). We would only use d4T+3TC today when neither AZT nor TDF could be used due to co-morbidity, for example in renal disease, anemic patients, in whom a HRS is difficult to manage (accompanying infections, poor compliance). If therapy with d4T+3TC has been started, it should be rapidly replaced. Because ddI has to be taken on an empty stomach (whilst AZT is tolerated better when taken with a meal), and in particular due to the greater risk of gastrointestinal side effects, AZT+ddI is contraindicated. TDF+ddI are relatively toxic and, recently, many studies have shown lower efficacy (see also "Problems with Initial Therapies"). TDF+ABC is likely to be problematic due to rapid development of resistance. AZT+d4T and FTC+3TC are antagonistic. References on nucleoside and nucleotide analogs 1. Benson CA, van der Horst C, Lamarca A, et al. A randomized study of emtricitabine and lamivudine in stably suppressed patients with HIV. AIDS 2004, 18:2269-76. http://amedeo.com/lit.php?id=15577539 2. Bernasconi E, Boubaker K, Junghans C, et al. Abnormalities of body fat distribution in HIV-infected persons treated with antiretroviral drugs: J Acquir Immune Defic Syndr 2002, 31:50-5. http://amedeo.com/lit.php?id=12352150 3. Bonjoch A, Paredes R, Galvez J, et al. Antiretroviral treatment simplification with 3 NRTIs or 2 NRTIs plus nevirapine in HIV-1-infected patients treated with successful first-line HAART. J AIDS 2005, 39:313-6. http://amedeo.com/lit.php?id=15980691 4. Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of ART-related lipodystrophy. Lancet 1999, 354:1112-5. http://amedeo.com/lit.php?id=10509516 5. Carr A, Workman C, Smith DE, et al. Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: a randomized trial. JAMA 2002, 288:207-15. http://amedeo.com/lit.php?id=12095385 6. Chene G, Angelini E, Cotte L, et al. Role of long-term nucleoside-analogue therapy in lipodystrophy and metabolic disorders in HIV-infected patients. Clin Infect Dis 2002, 34: 649-57. http://amedeo.com/lit.php?id=11810598 7. Clumeck N, Goebel F, Rozenbaum W, et al. 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The ALBI trial: a randomized controlled trial comparing stavudine plus didanosine with zidovudine plus lamivudine and a regimen alternating both combinations in previously untreated patients infected with HIV. J Infect Dis 1999, 180: 351-8. http://amedeo.com/lit.php?id=10395849 62. Molina JM, Journot V, Morand-Joubert L, et al. Simplification therapy with once-daily emtricitabine, didanosine, and efavirenz in HIV-1-infected adults with viral suppression receiving a protease inhibitor-based regimen: a randomized trial. J Infect Dis 2005, 191:830-9. http://amedeo.com/lit.php?id=15717256 63. Molina JM, Marcelin AG, Pavie J, et al. Didanosine in HIV-1-infected patients experiencing failure of antiretroviral therapy: a randomized placebo-controlled trial. J Infect Dis 2005, 191:840-7. http://amedeo.com/lit.php?id=15717257 64. Moyle G, Baldwin C, Langroudi B, Mandalia S, Gazzard BG. A 48 week, randomized, open label comparison of three abacavir-based substitution approaches in the management of dyslipidemia and peripheral lipoatrophy. J AIDS 2003, 33: 22-28. http://amedeo.com/lit.php?id=12792351 65. Moyle G, Boffito M. Unexpected drug interactions and adverse events with antiretroviral drugs. Lancet 2004, 364:8-10. 66. Moyle GJ, Dejesus E, Cahn P, et al. Abacavir once or twice daily combined with once-daily lamivudine and efavirenz for the treatment of antiretroviral-naive HIV-infected adults: results of the ziagen once daily in antiretroviral combination study. J AIDS 2005;38:417-425. http://amedeo.com/lit.php?id=16518962 67. Moyle GJ, Sabin CA, Cartledge J, et al. A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. AIDS 2006, 20:2043-50. http://amedeo.com/lit.php?id=17053350 68. Opravil M, Hirschel B, Lazzarin A, et al. A randomized trial of simplified maintenance therapy with abacavir, lamivudine, and zidovudine in HIV infection. J Inf Dis 2002, 185:1251-1260. http://amedeo.com/lit.php?id=12001042 69. Peyriere H, Reynes J, Rouanet I, et al. Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases. J AIDS 2004, 35:269-73. http://amedeo.com/lit.php?id=15076241 70. Piscitelli SC, Gallicano KD. Interactions among drugs for HIV and opportunistic infections. N Engl J Med 2001, 344:984-96. 71. Podzamczer D, Ferrer E, Sanchez P, et al. Less lipoatrophy and better lipid profile with abacavir as compared to stavudine: 96-week results of a randomized study. J AIDS 2006 Nov 9; http://amedeo.com/lit.php?id=17106274 72. Pozniak AL, Gallant JE, DeJesus E, et al. Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naive patients: virologic, immunologic, and morphologic changes--a 96-week analysis. J AIDS 2006; 43: 535-40. http://amedeo.com/lit.php?id=17057609 73. Robbins BL, Srinivas RV, Kim C, et al. Anti-HIV activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-PMPA), Bis PMPA. Antimicrob Agents Chemother 1998, 42:612-7. http://amedeo.com/lit.php?id=9517941 74. Robbins GK, De Gruttola V, Shafer RW, et al. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003; 349: 2293-303. http://amedeo.com/lit.php?id=14668455 75. Rousseau FS, Wakeford C, Mommeja-Marin H, et al. Prospective randomized trial of emtricitabine versus lamivudine short-term monotherapy in HIV-infected patients. J Infect Dis 2003;188:1652-8. http://amedeo.com/lit.php?id=14639535 76. Rozenbaum W, Katlama C, Massip P, et al. Treatment intensification with abacavir in HIV-infected patients with at least 12 weeks previous lamivudine/zidovudine treatment. Antiviral Therapy 2001, 6:135-42. http://amedeo.com/lit.php?id=11491418 77. Saag MS, Cahn P, Raffi F, et al. Efficacy and safety of emtricitabine vs stavudine in combination therapy in antiretroviral-naive patients: a randomized trial. JAMA 2004, 292:180-9. http://amedeo.com/lit.php?id=15249567 78. Saravolatz LD Winslow DL, Collins G, et al. Zidovudine alone or in combination with didanosine or zalcitabine in HIV-infected patients with the AIDS or fewer than 200 CD4 cells per cubic millimeter. New Eng J Med 1996, 335:1099-1106. http://amedeo.com/lit.php?id=8813040 79. Schaaf B, Aries SP, Kramme E, Steinhoff J, Dalhoff K. Acute renal failure associated with tenofovir treatment in a patient with acquired immunodeficiency syndrome. Clin Infect Dis 2003, 37:e41-3. http://amedeo.com/lit.php?id=12884188 80. Schooley RT, Ruane P, Myers RA, et al. Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study. AIDS 2002, 16:1257-63. http://amedeo.com/lit.php?id=12045491 81. Shafer RW, Smeaton LM, Robbins GK, et al. Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003; 349: 2304-15. http://amedeo.com/lit.php?id=14668456 82. Shah SS, Rodriguez T, McGowan JP. Miller Fisher variant of Guillain-Barre syndrome associated with lactic acidosis and stavudine therapy. Clin Infect Dis 2003, 36:e131-3. http://amedeo.com/lit.php?id=12746793 83. Sosa N, Hill-Zabala C, Dejesus E, et al. Abacavir and lamivudine fixed-dose combination tablet once daily compared with abacavir and lami-vudine twice daily in HIV-infected patients over 48 weeks (ESS30008, SEAL). J AIDS 2005, 40:422-7. http://amedeo.com/lit.php?id=16280696 84. Spruance SL, Pavia AT, Mellors JW, et al. Clinical efficacy of monotherapy with stavudine compared with zidovudine in HIV-infected, zidovudine-experienced patients. A randomized, double-blind, controlled trial. Ann Int Med 1997, 126:355-363. http://amedeo.com/lit.php?id=9054279 85. Squires K, Pozniak AL, Pierone G, et al. Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection. Ann Int Med 2003, 139: 313-320. http://amedeo.com/lit.php?id=12965939 86. Squires KE, Gulick R, Tebas P, et al. A comparison of stavudine plus lamivudine versus zidovudine plus lamivudine in combination with indinavir in antiretroviral naive individuals with HIV infection: selection of thymidine analog regimen therapy (START I). AIDS 2000, 14: 1591-600. http://amedeo.com/lit.php?id=10983646 87. Staszewski S, Hill AM, Bartlett J, et al. Reductions in HIV-1 disease progression for zidovudine/lamivudine relative to control treatments: a meta-analysis of controlled trials. AIDS 1997, 11:477-483. http://amedeo.com/lit.php?id=9084795 88. Staszewski S, Keiser P, Montaner J, et al. Abacavir-lamivudine-zidovudine vs indinavir-lamivudine-zidovudine in antiretroviral naïve HIV-infected adults: a randomized equivalence trial. JAMA 2001, 285: 1155-1163. http://amedeo.com/lit.php?id=11231744 89. Stekler J, Maenza J, Stevens C, et al. Abacavir hypersensitivity reaction in primary HIV infection. AIDS 2006, 20:1269-74. http://amedeo.com/lit.php?id=16816555 90. Suo Z, Johnson KA. Selective inhibition of HIV-1 reverse transcriptase by an antiviral inhibitor, (R)-9-(2-Phosphonylmethoxypropyl)adenine. J Biol Chem 1998, 273:27250-8. http://amedeo.com/lit.php?id=9765248 91. Taburet AM, Piketty C, Chazallon C, et al. Interactions between atazanavir-ritonavir and tenofovir in heavily pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2004, 48:2091-6. http://amedeo.com/lit.php?id=15155205 92. Thompson M, Haubrich R, D Margolis D, et al. Differences in calculated glomerular filtration rate in efavirenz- or tenofovir-treated adults in ESS40006. Abstract 777, 13th CROI 2006, Denver. 93. Van Leeuwen R, Katlama C, Murphy RL, et al. A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients. AIDS 2003, 17:987-99. http://amedeo.com/lit.php?id=12700448 94. Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic HIV infection. A controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. N Engl J Med 1990; 322:941-9. http://amedeo.com/lit.php?id=1969115 Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Mechanism of action and efficacy NNRTIs were first described in 1990. As with the nucleoside analogs, the target enzyme is reverse transcriptase. However, NNRTIs bind directly and non-competitively to the enzyme at a position in close proximity to the substrate binding site for nucleosides. The resulting complex blocks the catalyst activated binding site of the reverse transcriptase. This, in turn, can bind fewer nucleosides, slowing polymerization down significantly. In contrast to NRTIs, NNRTIs do not require activation within the cell. The three available NNRTIs - nevirapine, delavirdine and efavirenz - were introduced between 1996 and 1998. Although studies such as the ACTG 241 or INCAS had already clearly demonstrated the superiority of triple therapy compared to double nuke therapy (D'Aquila 1996, Raboud 1999, Conway 2000), the "rise" of the NNRTIs was rather hesitant, and did not receive the media attention given to the PIs. This was due to the early observation that functional monotherapy with NNRTIs, i.e. the mere addition of a NNRTI to a failing regimen, showed practically no effect. There were also initial difficulties in dealing with the development of problematic resistance: the risk of resistance is not only very high, but it can also develop very rapidly. Once it occurs, it almost always indicates resistance to the entire class. Waiting too long, when there is insufficient suppression of viral load, is almost certain to lead to complete resistance to this class of drugs. One point mutation at position 103 (K103N) of the hydrophobic binding site is enough to eliminate the entire drug class! Resistance has now even been described in women who have taken a single dose of nevirapine as mother-to-child transmission prophylaxis. In large studies, the frequency of NNRTI mutations following, in some cases, a single perinatal nevirapine mono-prophylaxis was between 14 and worryingly 65 % (Cunningham 2002, Jourdain 2004, Johnson 2005). This is possibly promoted by the long half-life of NNRTIs (Muro 2005). Thus, it is recommended to stop NNRTIs a few days prior to the other drugs if treatment interruption is necessary (see chapter on Treatment Interruption). The rapid development of resistance is also reflected in the increasing number of primary transmitted resistances: in 2001/2002 almost 10 % of all acute infections in Europe had a NNRTI resistance (Wensing 2005). If a resistance is present, there is no need to start or continue treatment with a NNRTI - it will not change the immunological or virological status (Picketty 2004), because the ability of HIV to replicate is not reduced as much by NNRTI mutations as by some PI or NRTI mutations. Despite the problems with resistance, numerous studies have demonstrated that NNRTIs are extremely effective when combined with nucleoside analogs. The immunological and virological potency of NNRTIs in treatment-naïve patients is at least equivalent, if not superior, to that of PIs (Staszewski 1999, Torre 2001, Podzamczer 2002, Robbins 2003). Newer studies such as ACTG 5192 or FIRST appear to support the predominance (MacArthur 2006, Riddler 2006). In contrast to PIs, however, the clinical benefit has not yet been proven as the studies that led to the licensing of NNRTIs all used surrogate markers. The efficacy of NNRTIs in treatment-experienced patients is probably weaker in comparison to PIs (Yazdanpanah 2004). The simple dosing and the overall good tolerability have enabled nevirapine and efavirenz to become important components of HAART regimens, which are often even ranked above those containing PIs. Over the last few years, many randomized studies have demonstrated that it is possible to switch from a PI to a NNRTI if good virological suppression has already been achieved. The efficacy was sometimes even better on NNRTIs than on the continued PI regimen (see also "When to change HAART"). Like efavirenz, nevirapine is metabolized by the cytochrome p450 system. Nevirapine is an inducer, whereas efavirenz is an inducer and an inhibitor of p450. In the combination of efavirenz with saquinavir or lopinavir the effects are so strong that dosage adjustment is necessary. So far, no study has provided definitive evidence that one NNRTI is more potent than another. Although delavirdine no longer has any role, due to diverse reasons (see below), nevirapine and efavirenz have an equal standing. Cohort studies from the last few years suggest a slight superiority of efavirenz (Phillips 2001, Cozzi-Lepri 2002). However, these studies have only limited value as they included very heterogeneous patient groups. In treatment-naïve patients, the difference is small (Nunez 2002). In the 2NN Study ("The Double Non-Nucleoside Study"), nevirapine and efavirenz were compared for the first time in a large-scale randomized study (Van Leth 2004). In total, 1,216 patients received d4T+3TC with either nevirapine 1 x 400 mg, nevirapine 2 x 200 mg, efavirenz 1 x 600 mg or efavirenz 1 x 800 mg plus nevirapine 1 x 400 mg. The only significant virological difference was an advantage of the efavirenz arm over the double NNRTI arm, mainly due to higher toxicity in the latter. In the nevirapine arm with 1 x 400 mg, severe hepatic side effects occurred more frequently than in the efavirenz arm; on the other hand, lipids were more favorably influenced in the nevirapine groups. The hepatic toxicity associated with once-daily doses of nevirapine was almost exclusively observed in a single center in Thailand (Storfer 2005). 2NN as well as switch studies, such as NEFA (Martinez 2003), demonstrate that the choice of NNRTI should be based mainly on the different side effect profiles (see below), and patient-specific factors should also be taken into account (Recent review: Sheran 2005). A second generation NNRTI, etravirine, which is also effective against NNRTI-resistances, will be available for the first time in EAP programs in 2007. Individual agents Nevirapine (Viramune™) was the first licensed NNRTI. The combination with AZT+ddI is probably the oldest HAART combination of all. It was investigated in 1993, in the ACTG 193A Study, where it proved to be superior to monotherapy and dual therapy in severely immunocompromised patients. However, this was only true for progression and not for survival (Henry 1998). In addition, the AZT+ddI+nevirapine combination was well investigated in the INCAS and ACTG 241 Studies (Raboud 1999, D'Aquila 1996). Nevirapine has also been tested against PIs in randomized studies. In the Atlantic Study, combination with d4T+ddI was approximately as effective as indinavir (van Leeuwen 2003); given with AZT+3TC in the Combine Study, the trend was somewhat better than nelfinavir (Podzamczer 2002). The pharmacokinetics of nevirapine appear to allow once-daily dosing (Van Heeswijk 2000). Various studies such as 2NN or Atlantic have already successfully used 400 mg once daily (van Leeuwen 2003, Van Leth 2004), although this dosage has not yet been approved in all countries. A new extended-release formulation is currently being developed. Nevirapine causes elevation of liver enzymes in up to 20 %, which may occasionally be severe. Lead-in dosing is always required. One study which reported that lead-in dosing is not required if efavirenz was previously administered (Winston 2004) still requires confirmation. During the first eight weeks on nevirapine, biweekly monitoring of transaminases is recommended. A rash develops in 15-20 % of cases and leads to discontinuation in up to 7 % (Miller 1997). Prophylactic administration of antihistamines or steroids does not prevent the rash (GESIDA 2004, Launay 2004). In the case of an isolated rash or isolated elevation of transaminases (up to five times the upper limit of normal), treatment can usually be continued. But, caution when both occur simultaneously! It is recommended to stop treatment if a rash occurs together with even a slight elevation of transaminases (> 2-fold of norm). It is important to note that hepatotoxicity can still appear several months later (Sulkowski 2002). Patients with chronic hepatitis are at risk, as are women with a low body weight (Sulkowski 2000, Sanne 2005, Kappelhoff 2005). An increased risk has also been reported for patients with a preserved immune status. Women with CD4 cell counts above 250/µl have a 12-fold elevated risk (11 versus 0.9 %), and the FDA even issued a warning relating to this in 2004. In treatment-naïve patients, the cut-off for women is 250, for men 400 CD4 cells - nevirapine should not be introduced above these values. However, in recent months a few studies have not been able to reproduce the association with the immune status (Wolf 2006). In particular, the risk does not seem to be increased in treatment-experienced patients, who change to nevirapine, even when CD4 cell levels are good (De Lazzari 2006, Mocroft 2006). There does not appear to be any correlation between side effects and drug plasma levels (Kappelhoff 2005). There is probably a genetic disposition for reactions to nevirapine - associated with HLA type - (Martin 2005), and drug-transporter gene variants have been described (Haas 2006, Ritchie 2006). Permanent and significant ?GT elevations are very common, which may subject patients to false suspicions of excess alcohol consumption. Nevirapine has a good lipid profile. Studies such as Atlantic or 2NN, discovered comparably favorable lipid changes for cholesterol and triglycerides (Van der Valk 2001, Van Leth 2004), as well as with efavirenz albeit to a lesser extent (Fisac 2005). It is not clear whether these positive effects will have clinical relevance over time and actually help to prevent cardiovascular events. Efavirenz (Sustiva™ or Stocrin™) was the third NNRTI to be approved, and the first for which it could be shown that NNRTIs were at least as effective and probably even better than PIs in untreated or only short term treatment-experienced patients. The 006 Study showed a superiority of efavirenz over indinavir (Staszewski 1999). Since then, efavirenz has been compared to other drugs in many studies. Efavirenz almost always did well. In ACTG 5095, efavirenz in combination with AZT+3TC was better than abacavir (Gulick 2004); in ACTG 384 it was better than nelfinavir (Robbins 2003, Shafter 2003); and in AI424-034 it was at least as effective as atazanavir (Squires 2004). ACTG 5192 demonstrated superiority over lopinavir/r (Riddler 2006). Moderate CNS side effects are often typical for efavirenz, which should therefore be taken in the evening before sleeping. Patients should be warned about these side effects, which usually include dizziness and numbness, but may also manifest as vivid dreams or even nightmares. In addition, patients should be warned about potentially hazardous tasks such as driving or operating machinery. The side effects probably correlate with high plasma levels (Marzolini 2001), and black African patients in particular seem to have a genetic predisposition (Haas 2004). Studies show that efavirenz disrupts the sleep architecture (Gallego 2004). In one study, after four weeks of treatment with efavirenz, 66 % of patients complained of dizziness, 48 % of abnormal dreams, 37 % of somnolence and 35 % of insomnia (Fumaz 2002). Although these symptoms seem to resolve during the course of treatment, they may persist in about one fifth of patients (Lochet 2003). Efavirenz should then be replaced. Liver problems occur less frequently than with nevirapine, and lead-in dosing is not necessary. Once-daily dosing is safe due to the long half-life, and, in contrast to nevirapine, is also licensed. However, lipids are not as favorably affected as with nevirapine. Gynecomastia is also typical for efavirenz, which is not only a psychological burden, but can also be painful (Rahim 2004). In such cases, efavirenz should be replaced with nevirapine if possible. Efavirenz is contraindicated in pregnancy. In women of childbearing age, its use must be considered carefully and if pregnancy is a possibility, nevirapine is preferable. Table 2.2. Frequency of the most important side effects of nevirapine and efavirenz (The numbers are based on various studies referenced in this chapter) Nevirapine Efavirenz CNS side effects Rare 58-66 % Severe CNS side effects Very rare 5-7 % Hepatotoxicity 17 % 8 % Dyslipidemia No Frequent Gynecomastia No Occasional Rash 15 % 5 % Delavirdine (Rescriptor™) was, in April 1997, the second NNRTI to be licensed by the FDA. Due to the pill burden and the required three times daily dosing, delavirdine is currently rarely prescribed. Delavirdine is not licensed in Europe where, in 1999, an application for licensure was rejected due to insufficient efficacy data. Nevertheless, delavirdine is likely to be as effective as the other NNRTIs (Conway 2000). In DLV 21, AZT+3TC+delavirdine was tested against AZT+3TC and AZT+delavirdine on 369 mostly treatment-naïve patients. After one year, 68 % had a viral load below 50 copies/ml in the triple combination arm compared to less than 10 % in the other two arms (Conway 2000). Rash (30 %) probably occurs more frequently than with other NNRTIs. Delavirdine increases plasma levels of various PIs (Harris 2002). However, use of this as a strategy for boosting, has not been widely accepted. References on NNRTIs 1. Conway B. Initial therapy with protease inhibitor-sparing regimens: evaluation of nevirapine and delavirdine. Clin Infect Dis. 2000, Suppl 2:S130-4. http://amedeo.com/lit.php?id=10860897 2. Cozzi-Lepri A, Phillips AN, d'Arminio Monforte A, et al. Virologic and immunologic response to regimens containing nevirapine or efavirenz in combination with 2 nucleoside analogues in the I.Co.N.A.) study. J Infect Dis 2002, 185: 1062-9. http://amedeo.com/lit.php?id=11930316 3. Cunningham CK, Chaix ML, Rekacewicz C, et al. Development of resistance mutations in women receiving standard antiretroviral therapy who received intrapartum nevirapine to prevent perinatal HIV type 1 transmission: a substudy of pediatric ACTG 316. JID 2002, 186:181-8. http://amedeo.com/lit.php?id=12134253 4. D'Aquila RT, Hughes MD, Johnson VA, et al. Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. Ann Intern Med 1996, 124:1019-30. http://amedeo.com/lit.php?id=8633815 5. De Lazzari E, Leon A, Arnaiz J, et al. Risk of hepatotoxicity in virologically suppressed HIV patients switching to nevirapine according to gender and CD4 count. Abstract H1064, 46th ICAAC 2006, San Francisco. 6. Fisac C, Fumero E, Crespo M, et al. Metabolic benefits 24 months after replacing a protease inhibitor with abacavir, efavirenz or nevirapine. AIDS 2005, 19:917-25. http://amedeo.com/lit.php?id=15905672 7. Fumaz CR, Tuldra A, Ferrer MJ, et al. Quality of life, emotional status, and adherence of HIV-1-infected patients treated with efavirenz versus PI-containing regimens. J AIDS 2002, 29:244-53. http://amedeo.com/lit.php?id=11873073 8. Gallego L, Barreiro P, del Rio R, et al. Analyzing sleep abnormalities in HIV-infected patients treated with Efavirenz. Clin Infect Dis 2004, 38:430-2. http://amedeo.com/lit.php?id=14727217 9. GESIDA 26/02 Study Group. Failure of Cetirizine to prevent nevirapine-associated rash: a double-blind placebo-controlled trial for the GESIDA 26/01 Study. J Acquir Immune Defic Syndr 2004, 37:1276-1281. http://amedeo.com/lit.php?id=15385735 10. Gulick RM, Ribaudo HJ, Shikuma CM, et al. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med 2004, 350:1850-1861. http://amedeo.com/lit.php?id=15115831 11. Haas DW, Ribaudo HJ, Kim RB, et al. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS 2004;18:2391-2400. http://amedeo.com/lit.php?id=15622315 12. Haas DW, Bartlett JA, Andersen JW, et al. Pharmacogenetics of nevirapine-associated hepatotoxicity: an Adult AIDS Clinical Trials Group collaboration. Clin Infect Dis 2006, 43:783-6. http://amedeo.com/lit.php?id=16912957 13. Harris M, Alexander C, O'Shaughnessy M, Montaner JS. Delavirdine increases drug exposure of ritonavir-boosted protease inhibitors. AIDS 2002; 16: 798-9. 14. Henry K, Erice A, Tierney C, et al. A randomized, controlled, double-blind study comparing the survival benefit of four different reverse transcriptase inhibitor therapies (three-drug, two-drug, and alternating drug) for the treatment of advanced AIDS. ACTG 193A Study Team. J AIDS Hum Retrovirol 1998,19:339-49. http://amedeo.com/lit.php?id=9833742 15. Johnson JA, Li JF, Morris L, et al. Emergence of drug-resistant hiv-1 after intrapartum administration of single-dose nevirapine is substantially underestimated. J Infect Dis 2005, 192:16-23. http://amedeo.com/lit.php?id=15942889 16. Jourdain G, Ngo-Giang-Huong N, Le Coeur S, et al. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med 2004, 351:229-40. http://amedeo.com/lit.php?id=15247339 17. Kappelhoff BS, van Leth F, Robinson PA, et al. Are adverse events of nevirapine and efavirenz related to plasma concentrations? Antivir Ther 2005, 10:489-98. http://amedeo.com/lit.php?id=16038474 18. Launay O, Roudiere L, Boukli N, et al. Assessment of cetirizine, an antihistamine, to prevent cutaneous reactions to nevirapine therapy: results of the viramune-zyrtec double-blind, placebo-controlled trial. Clin Infect Dis 2004, 38:e66-72. http://amedeo.com/lit.php?id=15095233 19. Lochet P, Peyriere H, Lotthe A, Mauboussin JM, Delmas B, Reynes J. Long-term assessment of neuropsychiatric adverse reactions associated with efavirenz. HIV Med 2003, 4:62-6. http://amedeo.com/lit.php?id=12534961 20. MacArthur RD, Novak RM, Peng G, et al. A comparison of three highly active antiretroviral treatment strategies consisting of non-nucleoside reverse transcriptase inhibitors, protease inhibitors, or both in the presence of nucleoside reverse transcriptase inhibitors as initial therapy (CPCRA 058 FIRST Study): a long-term randomised trial. Lancet 2006, 368:2125-35. http://amedeo.com/lit.php?id=17174704 21. Martinez E, Arnaiz JA, Podzamczer D, et al. Substitution of nevirapine, efavirenz or abacavir for protease inhibitors in patients with HIV infection. N Eng J Med 2003; 349:1036-46. http://amedeo.com/lit.php?id=12968087 22. Martin AM, Nolan D, James I, et al. Predisposition to nevirapine hypersensitivity associated with HLA-DRB1*0101 and abrogated by low CD4 T-cell counts. AIDS 2005, 19:97-9. http://amedeo.com/lit.php?id=15627041 23. Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS 2001, 15: 71-5. http://amedeo.com/lit.php?id=11192870 24. Miller V, Staszewski S, Boucher CA, Phair JP. Clinical experience with non-nucleoside reverse transcriptase inhibitors. AIDS 1997, 11 (suppl A): S157-164. 25. Mocroft A, Lacombe K, Rockstroh J, et al. Risk of discontinuation of nevirapine due to toxicities in antiretroviral-naive and experienced patients with high and low CD4 counts. Abstract THAB0104, XVI IAC 2006, Toronto. 26. Muro E, Droste JA, Hofstede HT, et al. Nevirapine plasma concentrations are still detectable after more than 2 weeks in the majority of women receiving single-dose nevirapine: implications for intervention studies. J AIDS 2005; 39:419-421. http://amedeo.com/lit.php?id=16010163 27. Nunez M, Soriano V, Martin-Carbonero L, et al. SENC trial: a randomized, open-label study in HIV-infected naive individuals. HIV Clin Trials 2002, 3:186-94. http://amedeo.com/lit.php?id=12032877 28. Phillips AN, Pradier C, Lazzarin A, et al. Viral load outcome of non-nucleoside reverse transcriptase inhibitor regimens for 2203 mainly antiretroviral-experienced patients. AIDS 2001;15:2385-95. http://amedeo.com/lit.php?id=11740189 29. Piketty C, Gerard L, Chazallon C, et al. Virological and immunological impact of non-nucleoside reverse transcriptase inhibitor withdrawal in HIV-infected patients with multiple treatment failures. AIDS 2004, 18:1469-71. http://amedeo.com/lit.php?id=15199325 30. Podzamczer D, Ferrer E, Consiglio E, et al. A randomized clinical trial comparing nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients (the Combine Study). Antivir Ther 2002, 7:81-90. http://amedeo.com/lit.php?id=12212928 31. Raboud JM, Rae S, Vella S, et al. Meta-analysis of two randomized controlled trials comparing combined zidovudine and didanosine therapy with combined zidovudine, didanosine, and nevirapine therapy in patients with HIV. INCAS study team. J AIDS 1999, 22: 260-6. http://amedeo.com/lit.php?id=10770346 32. Rahim S, Ortiz O, Maslow M, et al. A case-control study of gynecomastia in HIV-1-infected patients receiving HAART. AIDS Read 2004, 14:23-4. http://amedeo.com/lit.php?id=14959701 33. Riddler SA, Haubrich R, DiRienzo G, et al. A prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection: ACTG 5142. Abstract THLB0204, XVI IAC 2006, Toronto. 34. Ritchie MD, Haas DW, Motsinger AA, et al. Drug transporter and metabolizing enzyme gene variants and nonnucleoside reverse-transcriptase inhibitor hepatotoxicity. Clin Infect Dis 2006, 43:779-82. http://amedeo.com/lit.php?id=16912956 35. Robbins GK, De Gruttola V, Shafer RW, et al. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003; 349: 2293-303. http://amedeo.com/lit.php?id=14668455 36. Sanne I, Mommeja-Marin H, Hinkle J, et al. Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects. J Infect Dis 2005;191:825-9. http://amedeo.com/lit.php?id=15717255 37. Shafer RW, Smeaton LM, Robbins GK, et al. Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003; 349: 2304-15. http://amedeo.com/lit.php?id=14668456 38. Sheran M. The NNRTIs efavirenz and nevirapine in the treatment of HIV. HIV Clin Trials 2005, 6:158-68. http://amedeo.com/lit.php?id=16192249 39. Squires K, Lazzarin A, Gatell JM, et al. Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J AIDS 2004; 36: 1011-1019. http://amedeo.com/lit.php?id=15247553 40. Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. NEJM 1999, 341:1865-73. http://amedeo.com/lit.php?id=10601505 41. Storfer S, Leith J, Piliero P, Hall D. Analysis of hepatic events within the 2NN study: controlling for ethnicity and CD4+ count at initiation of nevirapine therapy. Abstract PE9.6/2. 10th EACS 2005. Dublin. 42. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with HIV and the role of hepatitis C or B virus infection. JAMA 2000, 283: 74-80. http://amedeo.com/lit.php?id=10632283 43. Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections. Hepatology 2002, 35:182-9. http://amedeo.com/lit.php?id=11786975 44. Torre D, Tambini R, Speranza F. Nevirapine or efavirenz combined with two nucleoside reverse transcriptase inhibitors compared to HAART: a meta-analysis of randomized clinical trials. HIV Clin Trials 2001, 2: 113-21. http://amedeo.com/lit.php?id=11590519 45. Van der Valk M, Kastelein JJ, Murphy RL, et al. Nevirapine-containing antiretroviral therapy in HIV-1 infected patients results in an anti-atherogenic lipid profile. AIDS 2001, 15: 2407-14. http://amedeo.com/lit.php?id=11740191 46. Van Heeswijk RP, Veldkamp AI, Mulder JW, et al. The steady-state pharmacokinetics of nevirapine during once daily and twice daily dosing in HIV-1-infected individuals. AIDS 2000, 14:F77-82. http://amedeo.com/lit.php?id=10853971 47. Van Leeuwen R, Katlama C, Murphy RL, et al. A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients. AIDS 2003, 17:987-99. http://amedeo.com/lit.php?id=12700448 48. Van Leth F, Phanuphak P, Ruxrungtham K, et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet 2004, 363:1253-63. http://amedeo.com/lit.php?id=15094269 49. Wensing AM, van de Vijver DA, Angarano G, et al. Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: implications for clinical management. J Infect Dis 2005, 192:958-66. http://amedeo.com/lit.php?id=16107947 50. Winston A, Pozniak A, Smith N, et al. Dose escalation or immediate full dose when switching from efavirenz to nevirapine-based highly active antiretroviral therapy in HIV-1-infected individuals? AIDS 2004, 18:572-4. http://amedeo.com/lit.php?id=15090815 51. Wolf E, Koegl C, Theobald T, et al. Nevirapine-associated hepatotoxicity: no increased risk for females or high CD4 count in a single-centre HIV cohort. Abstract H1063, 46th ICAAC 2006, San Francisco. 52. Yazdanpanah Y, Sissoko D, Egger M, et al. Clinical efficacy of antiretroviral combination therapy based on protease inhibitors or NNRTIs: indirect comparison of controlled trials. BMJ 2004, 328:249. http://amedeo.com/lit.php?id=14742351 Protease inhibitors (PIs) Mechanism of action and efficacy The HIV protease cuts the viral gag-pol polyprotein into its functional subunits. If the protease is inhibited and proteolytic splicing prevented, non-infectious virus particles will result. With the knowledge of the molecular structure of the viral protease, the first protease inhibitors (PIs) were designed in the early nineties; these substances were modified in such a way that they fit exactly into the active enzyme site of the HIV protease (review: Eron 2001). Since 1995, protease inhibitors have revolutionized the treatment of HIV infection. At least three large studies with clinical endpoints have demonstrated the efficacy of indinavir, ritonavir and saquinavir (Hammer 1997, Cameron 1998, Stellbrink 2000). Although PIs have been criticized at times due to their frequently high pill burden and side effects (see below), they remain an essential component of HAART. With growing knowledge of the mitochondrial toxicity of nucleoside analogs and through the introduction of easy-to-take PIs, this class of drugs is currently experiencing a renaissance -even PI-only regimens are now being investigated. As with the NNRTIs, initially, there was competition among pharmaceutical companies to establish which PI had superior efficacy. Only a few comparative randomized studies have been performed. But even in the case of PIs, the differences observed so far are not so significant as to compromise individual members of this class. Two exceptions that have since been taken off the market are: the hard gel capsule saquinavir and ritonavir on its own. Boosted PI combinations are more effective than unboosted regimens (see below). Apart from gastrointestinal side effects and high pill burden, all PIs used in long-term therapy encounter problems - to a greater or lesser extent, all are associated with lipodystrophy and dyslipidemia (review: Nolan 2003). Cardiac arrhythmias (Anson 2005) and sexual dysfunction have also been attributed to PIs (Schrooten 2001), although the data does not remain unchallenged (Lallemand 2002). There is a high degree of cross-resistance between protease inhibitors, which was described before PIs were put on the market (Condra 1995). All PIs are inhibitors of the CYP3A4 system and interact with many other drugs (see "Drug Interactions"). Ritonavir is the strongest inhibitor, saquinavir probably the weakest. "Boosting" protease inhibitors - why and how? Ritonavir is a very potent inhibitor of the isoenzyme 3A4, a subunit of the cytochrome P450 hepatic enzyme system. Inhibition of these gastrointestinal and hepatic enzymes allows the most important pharmacokinetic parameters of almost all PIs to be significantly increased, or "boosted" (Kempf 1997): maximum concentration, trough levels and half-life. The interaction between ritonavir and the other PIs allows a reduction in the frequency and number of pills simplifying daily dosing and makes the resorption partially independent of food intake. Some PIs can now be used in twice-daily regimens and current trials are investigating the possibility of once daily dosing of many PIs. Boosting with ritonavir is usually indicated by the addition of an "/r" after the drug name. Boosting can be effective against resistant viral strains as a result of the elevated plasma drug levels (Condra 2000). Resistance is less commonly observed on boosted PIs, at least in patients naïve to antiretroviral therapy, as the genetic barrier is very high. Although most of the data available relates to lopinavir/r, this also applies to fosamprenavir/r (Eron 2006), atazanavir/r (Malan 2006) and saquinavir/r (Ananworanich 2006). Boosting nelfinavir with ritonavir is not useful as plasma levels do not rise significantly (Kurowski 2002). Ritonavir boosting is also associated with risks as there is a very high degree of inter patient variability in plasma drug levels. Higher peak levels may lead to more side effects. If in doubt (reduced efficacy, side effects), plasma drug levels should be measured in all cases of boosting, especially in patients with severe hepatic diseases. Furthermore, apart from boosted atazanavir, all other boosted combinations appear to increase lipid levels (Van der Valk 2003). Table 2.3: Current doses of protease inhibitors with ritonavir boosting. Dose (mg) Pills*/day Comment Atazanavir/r 1 x 300/100 1 x 3 Only approved for treatment-experienced patients Darunavir/r 2 x 600/100 2 x 3 Only available in EAP** Fosamprenavir/r 2 x 700/100 2 x 2 Should be used instead of amprenavir Fosamprenavir/r 1 x 1400/200 1 x 4 Only approved for PI-naïve patients Indinavir/r 2 x 800/100 2 x 3 High rate of nephrolithiasis (?) Lopinavir/r 2 x 400/100 2 x 3 Only fixed booster combination Lopinavir/r 1 x 800/200 1 x 6 Currently only licensed in the USA Saquinavir/r 2 x 1000/100 2 x 3 Officially licensed for boosting Tipranavir/r 2 x 500/200 2 x 4 Only approved for treatment-experienced patients * Number of pills including the ritonavir dose. **EAP = expanded access program Individual agents Amprenavir (Agenerase™) was the fifth PI to enter the European market, in June 2000. Due to the further development of fosamprenavir (Telzir™, see below), it was replaced in 2004 (Rodriguez 2004). Only the suspension and the 50 mg tablet are available for children. Atazanavir (Reyataz™) was the first once-daily PI to be licensed in 2004. It is currently only licensed for treatment-experienced patients. In order to expand the license, atazanavir is being tested in therapy-naïve patients against lopinavir. In Phase II studies, atazanavir was better tolerated than nelfinavir, although the antiretroviral potency was comparable (Murphy 2003, Sanne 2003). In a Phase III study, atazanavir had a virological efficacy equivalent to efavirenz (Squires 2004). Unboosted atazanavir is slightly less effective than lopinavir in treatment-experienced patients (Cohen 2005). This does not seem to be the case if boosted, at least when PI resistance is limited (Johnson 2006). The primary resistance mutation for this drug is I50L, which does not impair sensitivity to other PIs, and possibly even increases it (Colonno 2003). On the other hand, there are a number of cross-resistance mutations, and susceptibility to many virus isolates with moderate PI resistance is reduced (Schnell 2003). In contrast to other PIs, atazanavir does not have a negative influence on lipid profiles (Sanne 2003, Squires 2004, Johnson 2006), which is its main advantage besides the once-daily dosing. It has been shown that lipids improve when other PIs are replaced by atazanavir (Wood 2004, Gatell 2006). It also does not induce insulin resistance (Noor 2004). In our experience, it is still questionable whether this will be reflected clinically with less lipodystrophy, as suggested in some studies (Haerter 2004, Jemsek 2006). In contrast to earlier reports, boosting of atazanavir with ritonavir does have negative effects on lipid levels (Malan 2006). Atazanavir should always be boosted with ritonavir in combinations with NNRTIs or tenofovir, which significantly lower atazanavir levels (Le Tiec 2005). Furthermore, unfavorable interactions occur particularly in combination with proton pump inhibitors (see "Drug Interactions"). One problem with atazanavir is that more than half the patients experience elevated bilirubin levels, which can reach grade 3-4 in approximately one third of all cases, and which occur more frequently with boosting (Squires 2004, Malan 2006). Some patients develop clinical jaundice. The mechanism for this resembles that of Gilbert's syndrome (and the increased levels with indinavir); there is reduced conjugation in the liver. Recently, a genetic predisposition has been identified (Rotger 2005). Although the hyperbilirubinemia is supposed to be harmless and only a few cases of serious hepatic disorders have been described to date (Eholie 2004), liver function should be monitored when on atazanavir, and treatment discontinued in cases of jaundice or significantly elevated bilirubin (> 5-6 times the upper limit of normal). Despite this, atazanavir is a PI, which in industrialized countries competes with lopinavir for the place of the most prescribed PI. Darunavir (Prezista, earlier TMC-114) is a PI, which was developed by the Belgian company Virco/Tibotec (since bought by Johnson & Johnson). In view of its significant efficacy against PI-resistant viruses (Koh 2003, King 2004), darunavir is currently one of the most interesting agents in HIV treatment. Two large Phase IIb studies, POWER 1 (USA) and 2 (Europe), led to the accelerated licensing of darunavir in June 2006 in the USA in treatment-experienced patients. The approval in Europe is expected in early 2007, and an expanded access program is already running. The POWER study included almost 600 patients. Pre-treatment was intensive, with three classes (median 11 drugs), and multiple resistance mutations at baseline. Several ritonavir-boosted doses of darunavir were tested against a boosted comparison PI. In the 600 mg group (600/100 bid), the viral load remained under 50 copies/ml in 46 % of patients, even after 48 weeks (Lazzarin 2006) - a significantly better result than with the control PI (10 %), and in a patient group that until now had extremely limited treatment options and no observable success. The results from POWER 3, a further, non-randomized study on long-term tolerability in 458 treatment-experienced patients, confirmed this response (Saag 2006). Of course the effectiveness of darunavir is not limitless. A total of 11 resistance mutations were identified in the POWER studies. Mainly found on codons 32, 47, 50 and 87 (DeMeyer 2006), three or more mutations significantly reduce the efficacy of darunavir. Darunavir is very usually well tolerated and the diarrhea may be milder than with other PIs (Lazzarin 2006). Dyslipidemias and elevation of liver enzymes, which occur with the main competitor PI tipranavir, appear to be less frequent. Relevant interactions exist with lopinavir, which decrease the plasma level of darunavir, and therefore the combination should be avoided. This also applies to combinations with sildenafil and some estrogen preparations. At present, numerous studies with darunavir are underway. It will be interesting to see the comparison studies between lopinavir on therapy-naïve (C211, ARTEMIS) and treatment-experienced (C214) patients, the results of which are not yet available. Darunavir is currently also being investigated in combination with etravirine (DUET study), and as a monotherapy. The full potential of this substance will only be revealed in the next two to three years. Fosamprenavir (Telzir™ or Lexiva™), as a calcium phosphate ester, has better solubility and absorption than amprenavir, reducing the number of pills to be taken. Fosamprenavir was licensed for treatment-naïve and -experienced patients in 2004. The possible doses are either a) 1400 mg bid (2 pills bid), b) 700 mg bid plus 100 mg ritonavir bid (2 pills bid) or c) 1400 mg plus 200 mg ritonavir once daily (4 pills qd). Once-daily dosing is not recommended for treatment-experienced patients, and, like the unboosted dose, is not licensed in Europe. One advantage of the drug is that there are no restrictions with respect to food intake, and it can be taken on an empty stomach or with a meal. Several studies have compared fosamprenavir to other PIs. In treatment-naïve patients in the NEAT Study, unboosted fosamprenavir was slightly more effective and had better tolerability than nelfinavir (Rodriguez-French 2004). However, high dropout rates limited this study. In the SOLO study, boosted once-daily fosamprenavir was about as effective as nelfinavir (Gathe 2004); this was also the case in comparison to atazanavir/r in the relatively small ALERT study (Smith 2006). No resistance mutations were found on fosamprenavir/r at 48 weeks (MacManus 2004). In the KLEAN study, in comparison to lopinavir there were no differences: severe diarrhea (13 versus 11 %) or increases in the cholesterol levels (11 versus 9 %) were no less rare on fosamprenavir (Eron 2006). In treatment-experienced patients in the CONTEXT Study, a somewhat (non-significant) reduced effect was seen with fosamprenavir/r in contrast to lopinavir/r (Elston 2004). Efavirenz and nevirapine as potent inducers of amprenavir metabolism, can significantly (probably with clinical relevance) lower plasma levels. This does not occur when fosamprenavir is boosted with ritonavir. Beware of the combination with lopinavir as plasma levels (AUC, Cmin) of both drugs are lowered! This unfortunately seems to eliminate what would otherwise have been an interesting salvage option (see " Interactions"). Indinavir (Crixivan™) is one of the oldest PIs, which was initially very successful in large studies (Gulick 1997, Hammer 1997). Later, indinavir had mixed success, at least when unboosted: in the Atlantic Study, it was about as effective as nevirapine (Van Leeuwen 2003), but in the 006 Study it was clearly weaker than efavirenz (Staszewski 1999). In the double blind, randomized CNAAB3005 Study, indinavir was more effective than abacavir, particularly in patients with high viral load at baseline (Staszewski 2001). In the CHEESE Study and MaxCmin1 studies, the efficacy was comparable to saquinavir-SGC (Cohen-Stuart 1999, Dragstedt 2003). Low protein binding (60 %) seems to allow better CNS penetration than with other PIs (Martin 1999). There are, however, a number of problems associated with indinavir. Firstly, it causes nephrolithiasis in approximately 5-25 % of patients (Meraviglia 2002), and thus requires good hydration (at least 1.5 liters daily). Unboosted indinavir must be taken three times daily on an empty stomach (Haas 2000), and for this reason, boosting with ritonavir is recommended - good pharmacokinetic data is available for 2 x 800/100 mg daily (Van Heeswijk 1999), although more side effects occur (Arnaiz 2004). In MaxCmin1, the dropout rate on indinavir/r versus saquinavir/r was notably higher (Dragstedt 2003). Specific side effects associated with indinavir include mucocutaneous side effects reminiscent of retinoid therapy: alopecia, dry skin and lips, and ingrown nails. Many patients may also develop asymptomatic hyperbilirubinemia. Although it seems that the dose and thus toxicity can be reduced in most patients by boosting and monitoring plasma levels, indinavir now has only a minor role in current antiretroviral regimens. Lopinavir/r (Kaletra™) is, since its licensing in April 2001, the first (and so far the only) PI with a fixed booster dose of ritonavir, which increases concentrations of lopinavir by more than 100 fold (Sham 1998). In the middle of 2006, the soft capsules, which had been used up until that time were replaced by tablets manufactured using melt extrusion technology("Meltrex"). This allowed a reduction to 2 x 2 tablets, and refrigeration of the tablets was not necessary. Since May 2005, in the USA, lopinavir/r has also been licensed for once daily administration, which is possibly equivalent in previously untreated patients (Johnson 2006). Large randomized studies are currently underway to compare the soft capsules with the tablets. It is still unclear whether the results of the earlier studies with the capsules can be equally applied to the tablets. They should nevertheless be briefly outlined. In treatment-naïve patients in a randomized double-blind study, lopinavir/r was significantly superior to unboosted nelfinavir (Walmsley 2002). This does not seem to be the case for other PIs, such as fosamprenavir (Eron 2006) and possibly saquinavir (Slim 2006). In ACTG 5142, lopinavir/r was even inferior to efavirenz (Riddler 2006), possibly because of the worse tolerability. In treatment-experienced patients in an open-label randomized (MaxCmin2) trial on a heterogeneous population lopinavir/r showed better results than boosted saquinavir (in the old Fortovase™ formulation). This was particularly true for tolerability and efficacy (Dragstedt 2005). In contrast, in two randomized studies, it was virologically no better than atazanavir (Johnson 2006) or fosamprenavir (Elston 2004) - although the patient numbers in these studies were relatively small. Development of resistance on lopinavir/r first-line therapy is rare, but is theoretically possible (Kagan 2003, Conradie 2004, Friend 2004). Lopinavir/r has a high genetic barrier to resistance, and it is likely that at least 6-8 cumulative PI resistance mutations are necessary for treatment failure (Kempf 2002). Lopinavir/r monotherapy, is therefore currently being intensively investigated (see Chapter 6). Gastrointestinal side effects (diarrhea, nausea), are commonly described but are significantly less on the new formulation. Lipodystrophy and dyslipidemia, occurs more frequently than with nelfinavir (Walmsley 2002), but no more than with fosamprenavir. A number of interactions should also be considered (see "Interactions"). The dose must be increased in combination with efavirenz and nevirapine. Nelfinavir (Viracept™) was, in 1998, the fourth PI on the market and was for a long time one of the most frequently used PIs. The dose of five capsules twice daily is as effective as three capsules three times daily. Boosting with ritonavir does not improve the plasma levels (Kurowski 2002). The most important side effect of nelfinavir is diarrhea, which may be considerable. The drug is otherwise very well tolerated. In the pivotal 511 Study, 61 % of patients on nelfinavir (with AZT+3TC) had a viral load below 50 copies/ml at 48 weeks (Saag 2001). In the open-label, randomized CNAF3007 Study, the decrease in viral load was comparable to abacavir (Matheron 2003). In comparison to NNRTIs or other PIs, nelfinavir is probably slightly less potent. In the Combine Study, nelfinavir was weaker (not significantly) than nevirapine (Podzamczer 2002). In ACTG 384 and 364, nelfinavir was inferior to efavirenz in both treatment-naïve and treatment-experienced patients (Albrecht 2001, Robbins 2003). This was also the case in comparison to lopinavir/r in the double blind, randomized M98-863 Study (Walmsley 2002). Nelfinavir is only rarely effective if a PI-containing therapy has failed (Lawrence 1999, Hammer 2002). In a few studies, nelfinavir was combined with saquinavir, which then significantly elevated plasma levels and thereby partially increased the efficacy (Moyle 2000, Chavanet 2001). However, such a combination is no longer acceptable due to the high pill burden and high incidence of diarrhea. Ritonavir (Norvir™) was the first PI for which efficacy was proven on the basis of clinical endpoints (Cameron 1998). However, ritonavir is now obsolete as a single PI, since tolerability is too poor. As gastrointestinal complaints and perioral paresthesias can be very disturbing, ritonavir is now only given to boost other PIs. The "baby dose" used for this purpose (100 mg bid) is tolerated better. Ritonavir inhibits its own metabolism via the cytochrome P450 pathway. The potent enzyme induction results in a high potential for interactions; thus, many drugs are contraindicated for concomitant administration with ritonavir. Metabolic disorders occur more frequently than with other PIs. Caution should be exercised in the presence of impaired liver function. It is important to inform patients that ritonavir capsules must be stored at cool temperatures, which can often be a problem when traveling. Saquinavir (Invirase 500™, previously Invirase™, Fortovase™) was, in December 1995, the first PI to be licensed for HIV therapy and is still today one of the few substances whose efficacy has been proven based on clinical end points (Stellbrink 2000). Boosting with ritonavir raises the plasma level considerably (review: Plosker 2003). The same applies to a simultaneous food intake. Saquinavir is well tolerated - there are hardly any serious side effects. With no serious short-term problems, Saquinavir is an attractive PI for patients who need a boosted PI-regimen. The earlier hard gel (Invirase™) and soft gel (Fortovase™) capsules were replaced in 2005 by Invirase 500™ tablets, which through the same pharmacokinetics (Bittner 2005), significantly reduced the number of pills to six a day (2 x 2 à 500 mg plus 2 x 100 mg ritonavir). It is possible that a lot of data from the time of Fortovase™ are probably not easily transferable to the Invirase 500™, but should be briefly mentioned. In the CHEESE Study, there was no difference between saquinavir soft gel and indinavir (Cohen-Stuart 1999). In MaxCmin1, in which saquinavir as well as indinavir were boosted with ritonavir, both demonstrated similar efficacy, although saquinavir was tolerated better (Dragstedt 2003). In MaxCmin2, boosted saquinavir-SGC compared slightly less favorably to lopinavir/r (Dragstedt 2005). In Staccato, a trial from Thailand, 89 % of all patients achieved a viral load below 50 copies/ml after 24 weeks (Ananworanich 2005) on a once-daily regimen (1,600 saquinavir/100 mg ritonavir). With the Invirase 500™ tablet, saquinavir has once again become an interesting option, due to its good tolerability. The preliminary data from the GEMINI study at least seem to indicate the absence of any serious inferiority to lopinavir/r (Slim 2006). Tipranavir (AptivusÒ) - the first non-peptidic PI - was licensed in July 2005 for pre-treated patients. In order to improve the oral bioavailability, tipranavir should be boosted with 2 x 200 mg (2 x 2) ritonavir (McCallister 2004). It is recommended that it be taken with food. A high-fat meal raises the plasma levels. Tipranavir has good efficacy against PI-resistent viruses (Larder 2000). For the licensing, two randomised Phase III studies were performed (RESIST-1 in the US and -2 in Europe) on 1,483 intensively pretreated patients. All patients received either tipranavir or a comparison PI, each combined with optimized background therapy (OBT). After 48 and 96 hours, tipranavir was immunologically and virologically superior to the comparison arm (Hicks 2006, Gazzard 2006). Good efficacy is maintained with up to 8 mutations in the RT gene as well as when less than 3 key PI mutations (L33I/V/F, V82A/F/L/T, I84V, and L90M) are present (Hall 2003, Baxter 2006). Tipranavir has therefore become an important option in salvage therapy. There is currently no license for use in therapy-naïve patients. The increases in triglycerides were more marked in the tipranavir group of the RESIST studies than in the comparison PIs (grade 3-4 increases/100 treatment years; 31% versus 23%), and transaminases were also significantly raised in some cases (GPT grade 3-4: 10% versus 3%). However, the incidence of unwanted side effects leading to discontinuation was comparable in both groups (Hicks 2006). 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The steady-state plasma pharmacokinetics of indinavir alone and in combination with a low dose of ritonavir in twice daily dosing regimens in HIV-1-infected individuals. AIDS 1999, 13: F95-9. http://amedeo.com/lit.php?id=10513637 82. Van Leeuwen R, Katlama C, Murphy RL, et al. A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients. AIDS 2003, 17:987-99. http://amedeo.com/lit.php?id=12700448 83. Voigt E, Wickesberg A, Wasmuth JC, et al. First-line ritonavir/indinavir 100/800 mg twice daily plus nucleoside reverse transcriptase inhibitors in a German multicentre study: 48-week results. HIV Med 2002, 3:277-282. http://amedeo.com/lit.php?id=12444946 84. Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med 2002, 346:2039-46. http://amedeo.com/lit.php?id=12087139 85. Wood R, Phanuphak P, Cahn P, et al. Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir. J AIDS 2004, 36:684-692. http://amedeo.com/lit.php?id=15167287 Entry inhibitors There are three crucial steps for entry of HIV into the CD4 cell: 1. Binding of HIV to the CD4 receptor, 2. Binding to co-receptors, and finally 3. Fusion of virus and cell. Every step of HIV entry can theoretically be inhibited. All three drug classes, namely attachment inhibitors, co-receptor antagonists and fusion inhibitors (FIs) are currently summarized as entry inhibitors (see the following chapter). In 2003, Fuzeon™ - the first and so far only drug of this class - was licensed. T-20 (Enfurvitide, Fuzeon™) is the prototype of the FIs. Since May 2003, it has been licensed in Europe and the US for the treatment of HIV-1 infection in treatment-experienced adults and children over 6 years of age. It is preferable to treat patients within clinical studies, so that clinical experience with this new drug can be collected. As a relatively large peptide (36 amino acids) it has to be administered by subcutaneous injection (Review: Oldfield 2005). T-20 binds to an intermediate structure of the HIV gp41-protein, which appears during fusion of HIV with the target cell. In early studies on intravenous monotherapy, the fall in viral load was, dose dependent, between 1.6 and 2 logs (Kilby 1998 + 2002). The first studies on subcutaneous administration showed an effect at up to 48 weeks: however, it became obvious that those patients, who received additional new antiretroviral drugs to which they were susceptible did better (Lalezari 2000 + 2002). Two Phase III studies led to the licensing of T-20. TORO 1 ("T-20 versus Optimized Regimen Only") enrolled 491 extensively pretreated patients in North and South America, most with multiresistant viruses; in TORO 2, 504 patients in Europe and Australia were enrolled. Patients, on an optimized HAART regimen, either received 90 mg T-20 bid subcutaneously or none at all (Lalezari 2003, Lazzarin 2003). In TORO-1, the viral load fell on T-20 at 48 weeks by a median of 0.94 logs; in TORO-2 it was 0.78 logs (Nelson 2005). A clear benefit was seen with T-20 in combination with the new PIs such as tipranavir and darunavir. In the RESIST and POWER studies, the response rates of these agents were considerably improved with T-20 (Youle 2006). In the MOTIVATE studies with the CCR5 antagonist maraviroc, this was not the case (Nelson 2007, Lalezari 2007). The success of T-20 therapy should be monitored early on. Patients without a decrease in viral load of at least one log after 8-12 weeks will not benefit from T-20 (Raffi 2006), and can be spared the required two injections per day. It is also not recommended to inject double the dose just once a day: although 1 x 180 mg has the same bioequivalence (as measured by AUC) as the standard 2 x 90 mg dose, a recent study showed a trend towards a lesser decrease in viral load with the 180 mg dose that was clearly associated with lower trough levels (Thompson 2006). Unexpectedly, a new occurrence under T-20 in the TORO studies was the increased frequency of lymphadenopathy and bacterial pneumonia (6.7 versus 0.6/100 patient years) (Trottier 2005). Septicemia also occurred more often, but the difference was again not significant. The reason for the increased rate of infections has so far remained unclear, but binding of T-20 to granulocytes has been suspected. Substantial side effects remain almost obligatory (98 % in TORO 1/2), and severe local skin reactions can sometimes occur at the injection site. They can be particularly painful, and result every so often in interruption of therapy: 4.4 % of cases in the TORO studies. In our experience of everyday clinical treatment, therapy is interrupted much more frequently due to the skin problems over a short or long time. After a certain amount of time, many patients refuse to continue with T-20 or to restart an interrupted therapy. Local reactions (see "Side Effects") can be reduced by using a bioinjection system, in which T-20 is pressed into the skin (Harris 2006). Resistance mutations develop relatively rapidly on T-20, but seem to reduce viral fitness (Lu 2002, Menzo 2004). Receptor tropism of the virus seems to be less significant than initially thought. Many more seem to have changes to a short sequence on the gp41 gene, causing reduced susceptibility; this requires only simple point mutations (Mink 2005, Melby 2006). However, viruses resistant to conventional HAART (NRTIs, NNRTIs, PIs) are susceptible (Greenberg 2003). As T-20 is a relatively large peptide, it induces antibody production. However, this does not impair the efficacy (Walmsley 2003). More disturbing, is the fact that, in a large TDM study, there were big differences between individuals, and extremely low plasma levels were usually measured (Stocker 2006). In summary: patients with a well-controlled viral load or who still have options with "classical" HAART do not require T-20. For salvage therapy, however, it remains a viable option. It is academically interesting to consider its potential in increasing HAART to empty latent reservoirs (Lehrmann 2005, Molby 2006). The price remains an important aspect of T-20. The company claims that it is one of the most complicated drugs it has ever manufactured, thus doubling the cost of HAART. This is unlikely to change even if an improved agent becomes available - the company is currently working on an improved formulation (but not pegylation) of T-20, which would allow weekly dosing. References on T-20 1. Greenberg ML, Melby T, Sista P, et al. Baseline and on-treatment susceptibility to enfuvirtide seen in TORO 1 and 2 to 24 weeks. Abstract 141, 10th CROI 2003, Boston. 2. Harris M, Joy R, Larsen G, et al. Enfuvirtide plasma levels and injection site reactions using a needle-free gas-powered injection system (Biojector). AIDS 2006, 20:719-23. http://amedeo.com/lit.php?id=16514302 3. Hicks CB, Cahn P, Cooper DA, et al. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the RESIST studies: an analysis of combined data from two randomised open-label trials. Lancet 2006, 368:466-475. http://amedeo.com/lit.php?id=16890833 4. Kilby JM, Ho