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HIV Therapy 2007

6. How to Start with HAART

by Christian Hoffmann and Fiona Mulcahy

Once the decision has been made that HAART is necessary, the next question is: what to start with? Because more than two dozen drugs are now available, the number of theoretically possible combinations at first sight seems to be very complex. In many guidelines, dozens of different combinations are recommendable or at least advisable.

Thus, it is preferable that every treatment-naïve patient participates in a clinical study, because only then can HAART be improved further. However, every now and then clinical trials are not possible. For these patients, the data available to date needs to be summarized.

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Recommended initial regimens Combinations that we currently recommend for first-line therapy (as of January 2007) are shown in Table 6.1. Table 6.1: Combinations suitable for initial HIV therapy (not in order of preference!) NRTIs NNRTI/PI *TDF + 3TC Lopinavir/ritonavir *TDF + FTC plus either Fosamprenavir/ritonavir **ABC + 3TC Efavirenz*** Nevirapine**** Alternatives Alternatives AZT + 3TC Saquinavir/ritonavir AZT + FTC * Convincing data only on combination with efavirenz. ** Combination with NNRTIs without HLA typing, may be problematic due to allergies. *** Caution should be taken in women of child-bearing age (teratogenicity) **** Caution with high CD4-cell counts (women > 250/µl, men > 400/µl) because of hepatotoxicity. Moreover, numerous other combinations are, of course, possible and licensed. These combinations are certainly not wrong, and may be acceptable in individual cases or in investigational studies, but general recommendations for their use cannot be given. Problematic combinations, that are not advisable for use, are listed at the end of this chapter. Practical approach to the first regimen - important rules All current initial regimens consist of two NRTIs, combined with either a boosted PI, an NNRTI or - with distinct restrictions - a third NRTI. No single combination has clearly been shown to be superior to another: there is no gold standard. When choosing primary therapy, many factors are involved, besides the antiviral potency and tolerability. Individual compliance, concurrent illnesses and concomitant medications, and the needs of the patient should be included in the decision. One should be aware that a primary therapy is of great significance and needs to be well prepared. It is at this time that the chance of viral suppression is greatest. Practical tips for first-line therapy: § The first regimen offers the patient the best chance. This means that the viral load must decrease to below detection levels within 3-6 months! § Don't rush - the patient must be ready for HAART, no half-hearted start! If in doubt, wait and continue to monitor the levels. § If possible, don't prescribe medication in the first consultation with a new patient. Do you know the patient well enough? Is he really motivated? Will he ever come back again? § For every patient, only prescribe the ART he is able to take! Don't insist on theoretically superior combinations. § The pros and cons (side effects) of different combinations should be discussed - there is usually enough time for this. § The initial regimen should be taken no more then twice daily. Once-daily treatment should be considered if it is important for the patient. § The toxicity profiles should not overlap, if possible - never use several allergenic drugs simultaneously. § Ask about other medication (and drug consumption) - are relevant interactions to be expected? § Concomitant illnesses should also be checked - what about the liver (hepatitis), kidneys? § All drugs are started on the same day - no lead-in mono- or dual therapy! § Be sure to check whether the patient would be eligible for a clinical study! All patients, especially if treatment-naïve, should be encouraged to participate in clinical trials! What should be clarified beforehand? Dosing issues Can the patient really take drugs reliably? Is this realistic with regard to his individual, professional or social situation? How regular is the patient's living, sleeping, and eating routine? If in doubt, a simpler regimen is preferable. For example, it is often not realistic to expect intravenous drug users to take tablets several times a day according to a strict protocol. There have been successful attempts at once-daily regimens for drug addicts (Staszewski 2000), which are also suitable for DOT (Directly Observed Therapy) together with methadone (a heroin substitute). For many patients, the numbers of pills or requirements for food intake are important. The range of licensed and recommended initial regimens varies from 2 to 13 pills per day. Some find it unacceptable to have to take pills at certain times during the day with fatty foods. Patients today are more demanding than earlier - justifiably so. There are now alternatives. Even the size or consistency of tablets can be a problem. Such issues must be discussed before initiating therapy. Concurrent illnesses Before starting treatment, a possible concurrent illness must be identified as it may effect drug choice. (see Table 6.2). For example, a patient with diarrhea may not tolerate nelfinavir, fosamprenavir, or lopinavir. ddI is contraindicated in patients with a history of pancreatitis! Caution with tenofovir or indinavir in renal disease! Polyneuropathy requires that any d-drugs (ddI, d4T) be avoided; they are only used as exceptions in primary therapy. Non-insulin-dependent diabetes can become insulin-dependent for the first time on PI treatment. The risk of developing severe hepatotoxicity on nevirapine or ritonavir is highest in patients with a history of liver disease and chronic hepatitis (Den Brinker 2000, Sulkowski 2000). Caution is also required with boosted PIs. However, one study conducted in over 1,000 patients found no difference between lopinavir/ritonavir and an unboosted PI such as nelfinavir in patients co-infected with hepatitis C (Sulkowski 2004). In co-infections with HBV, 3TC or FTC (not simultaneously!) in combination with tenofovir should ideally be used. Table 6.2: Concurrent illnesses requiring caution with specific drugs. There are no absolute contraindications. Illness Caution with Active hepatitis B Nevirapine, boosted PIs (In contrast: 3TC, FTC, tenofovir are beneficial!) Active hepatitis C Nevirapine, boosted PIs Active substance abuse, substitution NNRTIs, ritonavir Anemia AZT, possibly also 3TC Arterial hypertension Indinavir Chronic diarrhea, intestinal diseases Nelfinavir, lopinavir, fosamprenavir Diabetes mellitus PIs (especially if a NIDDM is at risk of becoming an IDDM!) Kidney disease Indinavir, tenofovir Myocardial infarction PIs (potentially beneficial: nevirapine) Pancreatitis ddI Polyneuropathy d4T, ddI Psychoses, other CNS illnesses Efavirenz Interactions with medications and drugs Interactions are important in the choice of combination regimens. Whereas interactions between antiretroviral drugs are well known, interactions with other concomitant medications are often less well characterized (see "Interactions"). The urgent need for more research was demonstrated in a study investigating the interactions between HAART and statins. In healthy volunteers, the measurement of plasma levels showed that levels of simvastatin were elevated by 3.059 % after concurrent dosing with ritonavir or saquinavir (Fichtenbaum 2002). One fatal rhabdomyolysis on simvastatin and nelfinavir has been described (Hare 2002). Many drugs should not be combined with particular antiretroviral drugs, as incalculable interactions may occur. These include certain contraceptives. Even drugs that seem unproblematic at first glance can have unfavorable effects: for example, the plasma levels of saquinavir can be reduced by half due to concurrent administration of garlic capsules (Piscitelli 2002). Even a seemingly harmless substance such as vitamin C can significantly lower indinavir levels (Slain 2005). Even warfarin can be a problem; ritonavir significantly lowers plasma levels (Llibre 2002). Further typical "problem drugs" include migraine remedies, prokinetic drugs and sedatives/hypnotics. One fatal case has been described with ergotamine and ritonavir (Pardo 2003). The simultaneous administration of HAART and PDE-5 inhibitors (sildenafil, vardenafil, tadalafil) can also be problematic (see "Sexual Dysfunction"). Drugs or alcohol can also interact with HAART. For those in substitution programs, the methadone requirement may be significantly increased by certain antiretroviral drugs such as nevirapine and efavirenz (Clarke 2001). To a lesser extent, this is also true for ritonavir and nelfinavir. There is inconsistent data on lopinavir, but it may also require dose adjustments (McCance-Katz 2003, Stevens 2003). Tenofovir does not seem to have significant interactions with methadone (Smith 2004). Other interactions have even more dangerous consequences. Several deaths have been reported after simultaneous dosing with ritonavir and amphetamines or MDMA/ecstasy, or the popular narcotic gamma hydroxybutyric acid (GHB, Samsonit™ or "liquid ecstasy"; Henry 1998, Harrington 1999, Hales 2000). Ritonavir in particular inhibits the metabolism of amphetamines (speed or MDMA/ecstasy), ketamines or LSD (review in: Antoniou 2002). Clinician and patient are well advised to have an open conversation about drug use before starting therapy. Marijuana and THC appear to have a low potential for interactions (Kosel 2002). Amphetamines seem to be particularly dangerous and neurotoxic in HIV patients (Langford 2003). Not every substance can be discussed here. Many are described in the respective drug chapters. It is always recommended to check the package insert. Initiation of HAART provides a good opportunity to re-evaluate existing prescribed medications. Additive toxicities Potential additive toxicities should also be considered in the choice of therapy. If other myelotoxic drugs (valganciclovir!) are necessary, caution is required with AZT. The same is true for dapsone and co-trimoxazole. When treating hepatitis C with interferon and ribavirin, ddI must be avoided, as well as AZT and d4T, where possible. Lastly, it is not advisable during the primary therapy to start with potential allergy-inducing substances if anti-infectious prophylaxis with co-trimoxazole or other sulphonamides is necessary. Included in this are nevirapine, efavirenz, and abacavir (and possibly fosamprenavir). In order not to disturb the prophylaxis, it is better to avoid these antiretroviral drugs; after all, one does have a choice. Otherwise, it can be difficult to clearly identify the causative agent for a drug-induced exanthema. Which drug classes are to be used? The combinations currently used as initial regimens consist of two nucleoside analogs plus either a PI or an NNRTI. A third nucleoside analog is only used in exceptional cases. All three strategies reduce the risk of AIDS approximately equally (Olsen 2005). In contrast, other combinations are experimental or not justified for use outside the framework of clinical studies. Advantages and problems of these three strategies are outlined in Table 6.3. Table 6.3: Combining drug classes: Advantages (é) and disadvantages (ê) 2 NRTIs + PI 2 NRTIs + NNRTI Triple Nuke é a lot of data, including clinical endpoints and severely immunocompromised patients é equivalent, perhaps even better suppression of viral load than with PIs é low pill burden, easy dosing é long-term data available é low pill burden! once-daily may be possible é leaves many options é high genetic resistance barrier é leaves PI options é few interactions ê higher pill burden (for the older PIs), partly strict dosing requirements, most once-daily regimens not licensed ê clinical effect not proven (only surrogate marker studies) ê less potent, with higher viral load, especially with tenofovir-containing triple nuke therapy ê frequent drug interactions ê less data in severely immunocompromised patients ê once-daily with AZT not possible ê some PIs with cross-resi-stance, leaving limited options ê rapidly occurring complete cross-resistance ê no clinical endpoints, no long-term data ê long-term toxicity, lipodys-trophy, dyslipidemia with most PIs ê strict monitoring required initially (esp. nevirapine), allergies frequent ê possible raised mitochondrial toxicity with three NRTIs There are only a few studies that directly compare all three of these strategies. In addition, the most tested combination is no longer used so that the validity of these studies is limited. This applies, for example, to the ATLANTIC study (van Leeuwen 2003) or the CLASS trial (Bartlett 2004), as well as to a few others (Gerstoft 2003). In 2006, a randomized trial on ACTG 5142 was published, in which the boosted PI lopinavir was tested against the NNRTI efavirenz (Riddler 2006) - two of the most used drugs at present. 753 therapy-naïve patients were included in this three-arm US study. Two groups were given two NRTIs (there was free choice and most received 3TC plus AZT, TDF or d4T-XR) and either lopinavir/r or efavirenz. The third group received an NRTI-free therapy with lopinavir/r and efavirenz. Table 6.4: ACTG 5142 - essential results after 96 weeks (Riddler 2006) Arm No treatment failure* Continuation of treatment < 50 (< 200) copies/ml CD4 increase EFV + 2 NRTIs 76 % 60 % 89 % (93 %) 241 LPV/r + 2 NRTIs 67 % 54 % 77 % (86 %) 285 EFV + LPV/r 73 % 61 % 83 % (92 %) 268 * defined as a viral load > 200 copies/ml or a drop of < 1 log after 32 weeks or change of treatment due to side effects The differences in the antiviral efficacy between EFV + NRTIs and LPV/r + NRTIs were significant; with less than 50 copies/ml after 96 weeks was approximately 12 %. The NRTI-free group was approximately in the middle of the other two groups. However, in the EFV + NRTI arm, the rate of virological failure was less - if the treatment did fail, resistance mutations in the LPV/r arms were more frequently seen, and the CD4 cells increased more on LPV/r than on EFV. The surprise was in the relatively good results of the NRTI-free arm. Thus, ACTG 5142 can still not provide a definitive answer and there remain pros and cons for each individual strtegy - the controversy about the best initial therapy persists. In the following, various strategies of primary therapy are discussed in more detail. These include: 1. Two NRTIs plus a NNRTI 2. Two NRTIs plus a protease inhibitor 3. Three NRTIs ("triple nuke") 4. Once-daily combinations 5. Experimental combinations ("nuke sparing", intensive approaches) 6. Problematic primary therapies, which should be avoided 1. Two NRTIs plus a NNRTI NNRTI-containing regimens have an at least equal, if not even better antiviral potency than PI combinations. NNRTIs have done well in numerous randomized studies. Efavirenz-based regimens were superior to indinavir, nelfinavir, amprenavir/r or triple nuke in studies such as 006, ACTG 384, ACTG 5095 or CLASS (Staszewski 1999, Robbins 2003, Gulick 2004, Bartlett 2004). Newer studies, such as ACTG 5142 (see above) or FIRST seem to support the superiority of NNRTIs (MacArthur 2006, Riddler 2006). Nevirapine-based regimens in COMBINE or ATLANTIC were at least equal to nelfinavir or indinavir, and better than triple nuke (Podzamczer 2002, van Leeuwen 2003). In the 2NN trial, there was no significant difference between efavirenz and nevirapine (van Leth 2004). Advantages of NNRTI-regimens include the low pill burden and good tolerability. In contrast to PIs, however, there is no study available with clinical endpoints. Neither is there any long-term data or studies on severely immunocompromised patients. Furthermore, a disadvantage of NNRTI combinations is the rapid development of cross-resistance. Allergies to NNRTIs are well described. Nevirapine, as it induces its own metabolism should be introduced in a phased increase over two weeks; with efavirenz, CNS disturbances are relatively common. TDF+3TC/FTC plus efavirenz (or nevirapine) In our opinion, this seems to be one of the preferable combination at present. In the double blind, randomized Gilead 903 Study, virological efficacy was equivalent to d4T+3TC (plus efavirenz), although tolerability was significantly better (Gallant 2004). Toxicity was reduced, and polyneuropathy, lipodystrophy and even dyslipidemia were significantly less frequent in the tenofovir arm. In the Gilead 934 Study, TDF+FTC plus efavirenz was more effective than AZT+3TC plus efavirenz after 48 weeks, because of tolerability (Gallant 2006). There is no reliable data on nevirapine in combination with TDF+3TC/FTC yet. For all TDF-containing combinations, care must be taken to monitor renal function on a monthly basis. AZT+3TC plus efavirenz or nevirapine These regimens were among those most frequently used and have been investigated in several large milestone trials (006, Combine, ACTG 384, 5095, 934). Side effects may occur during the first weeks, and normally trace back to AZT. In the 934 Study, anemia and gastrointestinal problems occurred frequently, which significantly compromised the efficacy of AZT+3TC in contrast to TDF+FTC (Gallant 2006, Pozniak 2006) More importantly it should be remembered that AZT has to be taken twice daily - once-daily dosing is not possible. d4T+3TC plus efavirenz or nevirapine Since the 903 Study (see above) and the ABCDE Study (Podzamczer 2006) the usefulness of d4T+3TC has become limited. This combination is only useful if renal problems or problems with hematopoiesis (anemia or thrombocytopenia) exist at the start of therapy. This applies, for example, to patients receiving chemotherapy or gancyclovir. In 2NN, d4T+3TC+efavirenz and d4T+3TC+nevirapine were approximately comparable (Van Leth 2004). 2. Two NRTIs plus a Protease Inhibitor This combination is the only HAART for which efficacy has been based on clinical endpoints in randomized studies (Hammer 1997, Cameron 1998, Stellbrink 2000). Data is also available for extended time periods, with some studies running for five years or more (Gulick 2003, Hicks 2003). Many experts choose these combinations in patients with AIDS or high viral load, in view of the robustness of boosted PIs to viral resistance. Disadvantages of the PI-containing primary therapy are the, sometimes high, pill burden and frequent side effects, both of which make compliance difficult. The most common combinations are: Two NRTIs plus lopinavir/r These are categorized in many guidelines as a combination that should be used in preference to other regimens. Long-term efficacy is good (Hicks 2003). So far, practically no resistance has been described in primary therapy. The combination of d4T+3TC+lopinavir/r was significantly better than d4T+3TC+nelfinavir in the only comparative study described to date. After week 48, 67 versus 52 % of patients had a viral load below 50 copies/ml (Walmsley 2002). Following studies such as KLEAN and Gemini, however, it appears that lopinavir/r is not more effective for initial therapy than other boosted PIs (Eron 2006, Slim 2006). According to ACTG 5142, efavirenz may be superior to lopinavir/r (Riddler 2006, see above). The nuke backbone used in most studies is currently TDF+FTC (Johnson 2006). ABC+3TC plus fosamprenavir/r ABC+3TC, in the combination Kivexa™, have been shown in the NEAT and SOLO studies to have good efficacy in combination with fosamprenavir (Gathe 2004, Rodriguez-French 2004). In the KLEAN study, there was no difference between fosamprenavir/r and lopinavir/r.in either efficacy or tolerability. Severe diarrhea or raised cholesterol were no less frequent (Eron 2006). In the ALERT study, fosamprenavir/r was approximately as effective as atazanavir/r with a backbone of TDF+FTC (Smith 2006). Two NRTIs plus saquinavir/r AZT+ddC+saquinavir was the first PI combination for which a survival advantage was shown (Stellbrink 2000). Nevertheless, saquinavir is still given with other NRTIs, rather than with AZT+ddC, and more importantly still, only in its boosted form (saquinavir/r 1,000/100 bid). Tolerability is probably better than for indinavir/r (Dragstedt 2003). More data is available for the AZT-containing nuke backbones than for those containing TDF. However, in the relatively small GEMINI trial, saquinavir/r with a TDF+FTC backbone did not appear to be much worse than lopinavir (Slim 2006). Two NRTIs plus nelfinavir Nelfinavir combinations were previously among the most frequently used ART regimens. The licensing studies mainly combined nelfinavir with AZT+3TC (Saag 2001, Gartland 2001). In Combine, there was a trend for nelfinavir to be slightly weaker than nevirapine (Podczamczer 2002); in INITIO it was clearly weaker than efavirenz (Yeni 2006). Even in direct comparison to boosted PIs such as lopinavir/r or fosamprenavir/r, nelfinavir is less potent (Walmsley 2002, Gathe 2004, Rodriguez-French 2004). Due to the high pill burden and the often substantial diarrhea, nelfinavir is generally no longer recommended for first-line therapy. 3. Three NRTIs - "Triple Nuke" Triple nuke therapies have advantages: few pills, few interactions, no side effects typical of PIs or NNRTIs, and the fact that all other drug classes can be spared for later. A big disadvantage is that triple nukes are virologically less potent than other combinations from several drug classes. With the growing knowledge about mitochondrial toxicity of NRTIs, some of the attractiveness of their use has been lost. AZT+3TC+ABC This combination in a single tablet of Trizivir™ (twice daily) is the classic triple nuke therapy. Trizivir™ is not as potent as other combinations from other drug classes. Initially, the combination with two NRTIs plus either unboosted PIs such as nelfinavir, atazanavir (Matheron 2003, Kumar 2006) or indinavir (Staszewski 2001, Vibhagool 2004) was accepted, but since ACTG 5095, Trizivir™ is no longer valid as a primary therapy (Gulick 2004). In this double blind, randomized study, 1,147 treatment-naïve patients received either AZT+3TC+ABC, AZT+3TC plus efavirenz, or AZT+3TC+ABC plus efavirenz. The endpoint was a viral load above 200 copies/ml after 16 weeks or later. After 32 study weeks, 21 % of patients in the Trizivir™ arm had a viral load above 200 copies/ml - in contrast to just 11 % in the other two arms. These differences were significant, and the triple nuke arm with AZT+3TC+ABC was discontinued. Trizivir™ is generally well tolerated - however, counseling on the abacavir hypersensitivity reaction is necessary. With respect to the AZT dose, the same applies for Trizivir™ as for Combivir™: it may be too high for some patients. TDF+3TC+ABC/ddI This combination should be avoided (Jemsek 2004, Gallant 2005, Khanlou 2005). There is a risk of treatment failure in up to 49 % of patients, probably due to a low genetic resistance barrier (Landman 2005). This also applies to treatment-experienced patients, who simplify HAART with this combination (Hoogewerf 2003, Perez-Elias 2005). TDF+AZT+3TC (+ABC) In retrospect, we ourselves have had good experience with TDF+AZT+3TC (Mauss 2005). Obviously, the thymidine analog of AZT is protective against tenofovir-associated mutations due to the various resistance pathways (Rey 2006, see also "Resistances"). Pilot studies have reported low viral failure rates on a quadruple therapy with TDF+AZT+3TC+ABC (Moyle 2006, Elion 2006); however, nothing is yet known about long-term toxicity and efficacy. Besides those involving Trizivir™ and tenofovir, a number of other triple nuke therapies have been tested, mostly with d4T and ddI (Gerstoft 2003, Van Leeuwen 2003, Bartlett 2004). They do not play any role in practice today. Summary: It is difficult for triple nukes to continue to carry the flag in primary therapy.. This option is only useful for patients with compliance problems or co-medications with the potential for interactions (tuberculosis or MAC therapy, marcumar) and low viral load. Triple nuke therapy also remains under consideration for maintenance therapy (see following chapter). 4. Once-daily combinations In recent years, many drugs have been licensed for administration once a day ("once-daily", OD; see Table 6.5). As a result, many once-daily options for primary therapy have emerged, such as TDF+FTC(3TC)+EFV (Saag 2004, Gallant 2006), ABC+3TC+EFV (Moyle 2005), and TDF+FTC+LPV/r (Johnson 2006). Table 6.4: Antiretroviral drugs and their usage in once-daily regimens (OD) Trade name Abbr. drugs OD? Comment Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) Combivirä AZT+3TC No Not possible due to AZT Emtrivaä FTC Yes Epivirä 3TC Yes Kivexa/Epzicomä 3TC+ABC Yes Retrovirä AZT No Not possible Trizivirä AZT+3TC+ABC No Not possible due to AZT Truvadaä FTC+TDF Yes Videxä ddI Yes Must be taken on an empty stomach Vireadä TDF Yes Zeritä d4T No d4T-XR is no longer coming Ziagenä ABC Yes Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Rescriptorä DLV No Not possible Sustiva/Stocrinä EFV Yes Viramuneä NVP Possibly A lot of data, OD-license planned NVP XR Protease inhibitors Aptivusä TPV/r No Not possible Crixivanä IDV/r No Little data available Darunavirä DRV/r Possibly Studies are underway Invirase 500ä SQV/r Possibly Studies are underway Kaletraä LPV/r Yes Licensed in the USA, not in Europe Reyatazä ATV/r Yes Also unboosted in the USA Telzir/Lexivaä FPV/r Yes Licensed in the USA, not in Europe Viraceptä NFV No Hardly any data available Fusion inhibitors Fuzeonä T-20 No OD not possible In theory, some experts still fear that once-daily regimens are unfavorable with respect to the development of resistance. If one dose is forgotten, a whole day of treatment is lost at once. These OD-regimens may therefore be problematic particularly in patients with poor compliance. However, if given within DOT programs (directly observed therapy), OD-regimens can be very helpful in this patient group (Staszewski 2000, Mitty 2005 + 2006). But, in the ACTG 5073 trial, DOT with a combination of lopinavir/r+FTC+d4T-XR produced no advantage, in fact the once-daily administration was less effective (Mildvan 2007). It is not yet clear whether once-daily dosing increases the compliance per se through such programs. In our experience, the step from three doses to two is bigger than from two to one. A meta-analysis (Claxton 2001) showed that the compliance was better on once-daily than on three or four-times daily dosing, but not better than twice-daily dosing (BID). There appears to be no difference between OD and BID if the BID regimens are simple and well tolerated (Stone 2004). Patients often would like to have once-daily regimens, but only when there are no dietary restrictions and the number of pills is low (Moyle 2003). Because of the quantity of tablets alone, despite the fairly good data available, several OD PI-combinations with saquinavir/r or lopinavir/r will never become popular (Mildvan 2007). The higher peak levels may also reduce the tolerability, as suggested by several studies. In the 418 Study, for example, once-daily lopinavir led to significantly more diarrhea than twice-daily doses (Johnson 2006). But, once-daily regimens not only affect the peak levels - the lengthened interval between doses also causes the trough levels to sink, especially with boosted PIs (Gibbons 2005). This can be relevant in treatment-experienced patients (Elston 2004, la Porte 2005), but should not be a problem in primary therapy. Summary: There is certainly no requirement for all patients to be treated with OD regimens. The wish of the patient should be considered. In particular, it may be difficult for individuals in employment with shift work, or with irregular lifestyles to take medication twice a day at set times. However, even these patients must be advised that it is just as important in once-daily regimens to take the medication on time. Experimental Combinations HAART has to become simpler and more tolerable. However, there is not always time to wait for new drugs to be developed! As a result, two approaches are currently being investigated: combinations without any NRTIs (nuke sparing), and so-called induction therapies, comprised of intensive combinations using more than three active drugs or drugs from three different classes. "Nuke sparing" Classical HAART regimens include a "backbone" consisting of two NRTIs (nuke backbone). This mainly has historical reasons: NRTIs were the first drugs on the market, and by the time NNRTIs and PIs were in development, treatment with two NRTIs was standard. With growing knowledge of the mitochondrial toxicity of NRTIs, nuke sparing, i.e. omission of NRTIs, even from the primary therapy, is being investigated more and more (see Table 6.6). A few studies on pre-treated patients have already tested nuke sparing successfully (see "When to change HAART"), and salvage therapy with double PI combinations is also being investigated. But for primary therapy? Since an NRTI-free combination of indinavir+efavirenz fared quite badly in the 006 Study (Staszewski 1999), nuke sparing initially seemed to be a thing of the past. But the pressure on NRTIs is increasing. The first large study to produce convincing data on nuke sparing was ACTG 5142 (Riddler 2006, see above). It showed that a combination of lopinavir/r and efavirenz was not worse than two NRTIs with either lopinavir/r or efavirenz. ACTG 5142 will definitely lead to further studies, and potentially in the mid-term to giving nuke sparing a firmer role in primary therapy than it has so far had. Apart from ACTG 5142 and 006, there have only been a few randomized studies to date. In EASIER, patients received indinavir/r and efavirenz with or without d4T. After 48 weeks, there were comparable effects with respect to the surrogate markers - and d4T did not have any additional effects. However, this study was compromised by the relatively high dropout rate (Stek 2003). Two small, randomized studies also found no significant difference between nuke sparing and standard regimens (Harris 2005, Cameron 2005). It is still unclear whether side effects really improve with nuke sparing. In HIVNAT009 it was reported that lipoatrophy resolved (Boyd 2003b); in CTN 177, nuke sparing had a favorable effect on lactate (Harris 2005). In ACTG 5142, the rate of lipoatrophy was reduced, but otherwise the tolerability was no better than on conventional regimens. Dyslipidemia was actually seen more frequently (Riddler 2006, Haubrich 2007). In view of the current data, it is still too early to recommend nuke sparing as an equally good approach. Table 6.6: Prospective studies on nuke sparing in treatment-naïve patients and patients with little prior treatment experience (intent-to-treat analyses) n (naïve) Combination (Study name) Proportion viral load < 50 copies/ml Staszewski 1999 148 (126)* EFV+IDV (006 Study) 47 % at 48 weeks Gisolf 2000 104 (104) SQV+RTV (Prometheus) 63 % at 48 weeks (< 400) Lopez-Cortez 2003 42 (0)** EFV+SQV/r 71 % at 52 weeks Stek 2003 47 (na)* EFV+IDV/r (EASIER) 53 % at 48 weeks Boyd 2003 61 (0)* EFV+IDV/r (HIVNAT 009) 69 % at 96 weeks Hellinger 2005 20 (4)* SQV+LPV/r (PIN) 70 % at 48 weeks Cameron 2005 16 (16) SQV+LPV/r (ACTG 384) 63 % at 48 weeks Allavena 2005 86 (65)* EFV+LPV/r (BIKS) 73 % at 48 weeks (< 400) Harris 2005 14 (14) NVP+LPV/r (CTN 177) 78 % at 48 weeks Ward 2006 63 (63) EFV+ATV/r (BMS 121) 63 % at 48 weeks Riddler 2006 253 (253) EFV+LPV/r (ACTG 5142) 83 % at 96 weeks *All PI-naïve. **22/42 less than 50 copies/ml at the time of switch. na = not available. Monotherapies, alternating therapies Does it get any easier? In the summer of 2003, an avant-garde concept was presented: monotherapy with boosted PIs. In view of the high resistance barrier of PIs, the success was, in part, promising (see "How to Change HAART"). Because of the always greater number of well-tolerated drugs, it is difficult to find sensible reasons for monotherapy in primary therapy. Another new approach is alternating therapy. In the SWATCH study, a total of 161 patients were randomized to a regimen of d4T+ddI+efavirenz or AZT+3TC+nelfinavir (Martinez-Picado 2003). A third arm changed between the two regimens every three months, as soon as the viral load was below the level of detection. After 48 weeks, virological failure in the alternating arm was significantly reduced. There was no difference for other parameters (CD4 cells, side effects). However, the good tolerability of other treatments has meant that such alternating therapies, which can confuse the patients completely, have lost their significance. More intensive (induction-) treatment with 4-5 drugs Over and over again, the question is brought up as to whether more intensive approaches than triple therapy combinations are necessary in patients with a high viral load. Due to a growing concern about the rapid development of resistance, some clinicians are starting to treat these patients with an "induction" of four or even five drugs, which are then simplified to a triple combination once the viral load has been well suppressed. This concept has not yet been validated, and is only based on theoretical hypotheses or smaller proof-of-concept studies in which it has been shown that the viral load sinks faster under intensive combinations than under standard therapies (Ramratnam 2004). Approaches in which multiple individual drugs are given have to be distinguished from approaches in which three instead of two classes of drugs are used. Multiple individual drugs: really have no advantages. Giving two PIs instead of one PI, or two instead of one NNRTI sometimes produced even negative results (Moyle 2000, Katzenstein 2000, van Leth 2004). There is also no argument in favor of giving three instead of two NRTIs (Staszewski 2003, Orkin 2004). In ACTG 5095, there was clearly no difference between Combivir™+efavirenz and Trizivir™+efavirenz; not even in highly viremic patients (Gulick 2005). More drug classes: The data on whether to use three or two drug classes is not so clear. ACTG 388: 517 relatively advanced HIV patients received indinavir, indinavir+efavirenz, or indinavir+nelfinavir (Fischl 2003). After two years, virological failure on indinavir+efavirenz was lower than in the other arms. The poorest results came from indinavir+nelfinavir. Thus, ACTG 388 showed an advantage of triple- over two-class therapy. However, some patients were treatment-experienced and around 10 % already had resistance mutations at baseline. ACTG 384: 980 patients were distributed between six treatment arms (Robbins 2003, Shafer 2003): either AZT+3TC or d4T+ddI combined with efavirenz, nelfinavir or efavirenz+nelfinavir. The NRTIs were blinded; the rest were given openly. Preliminary data after a follow-up of 28 months is confusing: AZT+3TC were more effective than d4T+ddI, but only in combination with efavirenz, not with nelfinavir. Conversely, efavirenz was superior to nelfinavir, but only with AZT+3TC as a backbone. The quadruple arm was better than all triple regimen arms combined, but not in comparison to the single most effective arm of AZT+3TC+efavirenz. INITIO: 911 patients received efavirenz, nelfinavir or efavirenz+nelfinavir, each with a backbone of d4T+ddI, in an open-label design. No difference was seen between the triple and quadruple arms (Yeni 2006). The main disadvantage of this long-term study was that the treatment regimens being studied became somewhat outdated, and dropout rates were correspondingly high as a result. ANRS 081: tested a triple-class regimen consisting of d4T+nevirapine+indinavir compared to a conventional d4T+3TC+indinavir regimen in 145 patients who were either treatment-naïve or had only little prior treatment experience. The triple-class arm fared worse. At week 72, 52 versus 79 % had a viral load below 20 copies/ml. 43 % discontinued the nevirapine therapy (Launay 2002). FIRST (CPCRA 058): 1,397 patients were given two NRTIs together with either a PI, a NNRTI, or a PI plus a NNRTI. Because the trial started more than five years ago, the most frequently-used PI was nelfinavir, and boosted PI regimens were rare. Despite the limited predictive strength, the NNRTIs were found to be superior (MacArthur 2006). Summary: in the studies cited, improved efficacy could not be demonstrated and increased side effects of the intensified regmens negatively impacted on adherence. Indeed, there is the risk of scaring patients away with the higher number of pills and side effects. It is still unclear whether in patients who first start with HAART at an advanced stage of their disease ("late presenters") such intensification of therapy is useful. 6. Unfavorable Primary Therapies Combinations considered to be suboptimal include all forms of mono- and dual therapy, especially two NRTIs. Even one NRTI plus one NNRTI is not good, as shown by the INCAS Trial (Montaner 1998). When using NRTIs, it is important to make sure that they are not competing for the same bases. Combinations of thymidine analogs (AZT+d4T) or cytidine analogs (FTC+3TC) make no sense. The thymidine analogs AZT and d4T are even antagonistic (Havlir 2000, Pollard 2002). ddC (HIVID™), saquinavir-SGC (Fortovase™) and amprenavir (Agenerase™), which have partially been taken off the market, should be avoided. T-20, darunavir, and tipranavir as well as delavirdine and atazanavir (in some countries) are not licensed for use in primary therapy. Ritonavir in full dose (not as boosting) can be rejected, as the tolerability is so poor. The much-used combination d4T+ddI, is also not recommended because of mitochondrial toxicity. Abacavir plus NNRTIs simultaneously: a new ABC-containing combination should not include a new NNRTI. Both can cause allergies, which are often difficult to distinguish from one another. In the case of abacavir, even a suspected allergy rules out re-exposure, so that an important drug may be unnecessarily and permanently lost. In CNA30024, 9 % of patients developed a hypersensitivity reaction on ABC+3TC+efavirenz (DeJesus 2004). NNRTI combinations: NNRTIs act non-competitively at the same site, and furthermore all can cause a rash, making differential diagnosis difficult. Efavirenz levels seem to be lowered considerably with nevirapine (Veldkamp 2001). In the wake of the 2NN Study, it finally seems clear that the combination of efavirenz and nevirapine should be avoided. The study arm with this combination fared worse than the other arms, mainly due to toxicity (Van Leth 2004). TDF-triple nuke: Tenofovir should not be administered as part of a triple nuke regimen. Too many studies have reported poor response rates, particularly in combination with ABC+3TC (Hoogewerf 2003, Jemsek 2004, Khanlou 2005, Gallant 2005). See "Triple Nuke". TDF+ddI: It is rare that a combination is discarded within only a few months with such a data collection: at least five trials, which tested TDF+ddI plus a NNRTI, resulted in a high failure rate of therapy, and some were stopped prematurely (Leon 2005, Podzamczer 2005, Maitland 2005, van Lunzen 2005, Torti 2005). The worst efficacy was observed in patients with a significant immune defect and high viral load. The company BMS even sent a warning letter concerning TDF+ddI. Meanwhile, there have also been reports of unfavorable effects on the CD4 cells, despite a good virological response. (Kakuda 2004, Barrios 2005). The reasons for this effect have not been fully explained. Reports of higher toxicity and in particular pancreatitis (Blanchard 2003, Martinez 2004, Masia 2005, Crane 2006), have been described and therefore the combination of TDF+ddI is no longer recommended. Starting gradually: All drugs should be started simultaneously. In several studies, significant differences were shown between patients who were started on three drugs simultaneously and those who were started on only two drugs (Gulick 1998, Ait-Khaled 2002). The risk of a virological treatment failure is doubled even after years if dual therapy is given for just a few weeks (Phillips 2002). There is no doubt: the "cautious approach", as is sometimes practiced due to concern over too many side effects, is unnecessary and dangerous. This also applies to the dosing - starting therapy should always be with the full dose (exception: nevirapine! See corresponding section). Avoidable mistakes in primary therapy § Mono- or dual therapy (except in controlled trials), as well as a slow introduction - always start with a complete HAART regimen! § Lowering the doses at the beginning (with the exception of nevirapine!) § T-20, delavirdine, tipranavir (not licensed for primary therapy) § ddC (HIVID™), SQV-SGC (Fortovase™), amprenavir (Agenerase™) - distribution has been partially stopped § Ritonavir (not tolerated - only for use as booster) § AZT+d4T and 3TC+FTC (antagonistic effects) § TDF+ddI (diverse reasons), d4T+ddI (too toxic) § TDF in triple nuke therapy (especially without thymidine analogs) § Simultaneous introduction of ABC and NNRTIs (allergy potential) § Efavirenz+nevirapine (too toxic) References 1. Ait-Khaled M, Rakik A, Griffin P, et al. Mutations in HIV-1 reverse transcriptase during therapy with abacavir, lamivudine and zidovudine in HIV-1-infected adults with no prior antiretroviral therapy. 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