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Corklin R Steinhart
Senior Attending Physician
The past few years have seen an explosion of new antiretroviral (ARV) medications that have been approved for use. However, a significant number of limitations remain for ARVs. For example, resistance to all ARVs has been shown to occur unless complete viral suppression can be obtained. Significant cross-resistance has been demonstrated with many of the medications, thus limiting their use once virological failure to one of them has occurred. In addition, short-term toxicities can occur with all currently available medications. This is particularly problematic, as antiretroviral therapy (ART) is clearly necessary for an indefinite period of time. Moreover, the association of long-term morphological and metabolic complications with combination ART (cART) plays a prominent role regarding time to initiate therapy. This also accounts for patients’ reluctance to begin ART. Both of these adverse associated effects are directly related to patient adherence, which is one of the major factors in ARV failure. The necessity of taking the medications on a daily basis, the lack of forgiveness if a dose is missed, multiple drug–drug interactions with several of the ARVs, especially the protease inhibitors (PIs), and, until recently, having to take many pills several times a day are also significant limitations to the use of the current armamentarium of HIV treatments. Perhaps the greatest limitation with the currently available ARVs is their inability to eradicate or cure chronic HIV infection.
There are currently 22 FDA-approved ARVs in four classes. In 2003 alone, four new ARVs in three different classes were approved for use, and 2004 saw the addition of two new, once-daily combination pills. A new PI, tipranavir (Aptivus) was FDA-approved in the USA in mid-June 2005. Clearly a wonderful advance in patient management, the appropriate use of these medications, however, is extremely difficult, even for the most experienced providers. Consequently, guidelines were developed both in the USA(1,2) and Europe;(3) these guidelines are regularly updated in order to help healthcare providers. In addition, the guidelines strongly recommend that clinicians with extensive experience provide HIV care. In this regard, several studies have demonstrated that patient outcome is directly related to the experience of the provider.(4–6)
Recent additions to existing drug classes
Nucleoside/nucleotide reverse transcriptase inhibitor combinations
Although no new nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) have been approved since emtricitabine (Emtriva) in August 2003, two new once-daily combination pills were approved last year. Emtricitabine and tenofovir DF (disoproxil fumarate) were combined as Truvada, and lamivudine and abacavir were combined as Epzicom. The availability of these medications has now further simplified the “nuke” backbone for cART, allowing for expanded options for true once-daily dosing with fewer pills. More importantly, the unprecedented agreement between Bristol-Myers Squibb (BMS) and Gilead Sciences to coformulate efavirenz (Sustiva, Stocrin) and Truvada as a single three-in-one once-daily pill will revolutionise ART for ARV-naive patients. It is expected that this combination pill may be available during the first quarter of 2006.
At the present time, the main question healthcare providers must answer is which one of these two combination medications should one start with as part of initial cART. Although most experts agree that both lamivudine and emtricitabine are essentially identical in safety, efficacy and resistance profiles, it is for the second component of each combination that controversy exists. Ardent discussions over varying resistance pathways that the virus may choose when virological failure occurs following initial therapy containing either abacavir or tenofovir DF remain heated. Perhaps more importantly, however, although both abacavir and tenofovir DF are very potent, have pharmacokinetics that allow for once-daily dosing and are generally very well tolerated, each drug has its problems that must be addressed when considering the use of either Epzicom or Truvada. With abacavir, the hypersensitivity reaction (HSR) occurring in 5–8% of patients(7,8) continues to be of concern, even to many seasoned HIV practitioners. The lack of negative drug–drug interactions of abacavir and its otherwise very favourable resistance and safety profiles nevertheless make its use in Epzicom very beneficial.
Although tenofovir DF has been thought to be an extremely safe ARV, recent concerns about its potential renal toxicity have been brought to light.(9–11) In addition, the propensity of tenofovir DF for drug–drug interactions if used, for example, with didanosine (Videx EC) or atazanavir (Reyataz) may limit its utility in some patients. Several reports of a blunted immunological response to cART when ddI and tenofovir DF are used together,(12,13) as well as a study(14) demonstrating an inferior virological response when tenofovir DF and didanosine were used as part of initial therapy compared with not using them together, have raised further concerns in the use of tenofovir DF when combined with some other ARVs. At the present time, however, the verdict remains unclear. Nevertheless, tenofovir DF as part of Truvada remains a very popular component of the simplified ARV regimens. Indeed, the 2005 DHHS Guidelines(15) have both tenofovir DF and emtricitabine as preferred initial NRTI drugs.
Atazanavir, which was approved in mid-2003, has pharmacokinetics that allow once-daily dosing, is generally not associated with dyslipidaemia like other agents in this class,(16,17) and may have less deleterious effects on glucose metabolism.(18) Atazanavir has demonstrated clinical efficacy comparable with the standard of care in ART-naive patients(19,20) and, when boosted with ritonavir, in lopinavir/r treatment-experienced patients.(21) Emergence of the I50L protease mutation, the signature mutation for atazanavir, resulting in marked decrease in atazanavir susceptibility, has been demonstrated to increase susceptibility to other PIs in vitro.(22) In contrast to the other PIs, atazanavir has a low pill burden and a simple dosing schedule, which may foster adherence to therapy. Coupled with its signature mutation, these characteristics have made atazanavir particularly attractive as first-line PI. However, in some patients it results in asymptomatic elevations of unconjugated bilirubin and jaundice of 45% and 7%, respectively.(23) Its pharmacokinetics are significantly affected by the concomitant administration of tenofovir DF, thus necessitating the use of ritonavir boosting. A 76% reduction in atazanavir area-under-the curve and a 78% reduction in atazanavir C(min) were observed when omeprazole 40mg was administered with atazanavir 300mg and ritonavir 100mg.(24) Coadministration of these agents is, therefore, not recommended by the manufacturer and may significantly limit its use. However, recent guidelines from BMS show that it can be administered with H(2)-blockers or antacids if dosed at appropriate intervals during the day.(25)
FDA-approved in late 2003, fosamprenavir (Lexiva) is the prodrug of amprenavir (which was approved in 1999), and therefore offers the significant advantage of a much reduced pill burden and improved gastrointestinal (GI) profile.(26) Several large studies, NEAT(27) and SOLO,(28) have demonstrated the safety and efficacy of fosamprenavir in ARV-naive patients. In PI-experienced patients, boosted fosamprenavir was shown not to be inferior to lopinavir/r, the current gold standard for PIs.(29) Although resistance- associated mutations at positions I54L/M, V32I, I47V and M46I have been detected in ARV-naive patients treated with fosamprenavir, no such mutations have been detected in naive patients treated with fosamprenavir/r.(28) As its signature mutation is the I54V mutation, it has the theoretical advantage of being able to be successfully sequenced when used as first-line PI. Although fosamprenavir has the same problems of drug–drug interactions as other PIs due to its effect on CYP3A4, it has recently been shown not to be affected by the concomitant administration of the proton pump inhibitor esomeprazole.(30) This is a significant advantage of fosamprenavir over its competitor, atazanavir, as described above. A clinical trial in naive patients comparing once-daily boosted atazanavir with boosted fosamprenavir is ongoing. Interestingly, the “backbone” NRTI is Truvada, even though the study is being sponsored by GlaxoSmithKline, the maker of Epzicom.
The most recently FDA-approved PI, tipranavir, is also the first PI approved for use in highly treatment-experienced patients or in patients with multiple PI-mutations.(31) Several excellent and thorough reviews(32–34) have been written, and space does not allow for any extensive review here. Tipranavir is a nonpeptidomimetic PI with unique binding characteristics at the protease enzyme binding site. Originally thought to be due to unusual flexibility of the molecule, it now appears that this is not the case, and other hypotheses have been brought forth.(35,36) In-vitro studies have demonstrated that it suppresses both laboratory and clinical isolates of HIV-1, including those highly resistant to the other peptidomimetic PIs. Resistance develops slowly as stepwise development of multiple PI mutations is required similar to most of the current PIs, and cross-resistance to all other PIs except for saquinavir has been demonstrated.(37) Indeed, a tipranavir-mutation score has been developed that has been suggested to help predict which PI- experienced patients are likely to respond.(38)
Tipranavir is both metabolised by and is an inducer of the cytochrome P450 3A4 isozyme and, therefore, must be “boosted” with ritonavir in order to achieve therapeutic drug levels. However, and unlike the use of ritonavir with other PIs, a higher dose of ritonavir must be used in order to achieve therapeutic drug levels. The coadministration of other CYP3A4 inhibitors is unlikely to affect the plasma concentration of tipranavir.(31)
Clinical efficacy has been aptly demonstrated at least for the short term (24 weeks) in highly treatment-experienced patients. In pivotal phase III trials, virological efficacy and treatment responses have been significantly better with tipranavir/r than with the comparator PIs used.(39,40) However, GI adverse events were greater in the tipranavir/r group, and both transaminase and lipid levels, although low overall, were significantly higher.(41) Of note, treatment responses were significantly enhanced if enfuvirtide (see below) was part of the optimised background regimen (OBR). Similar to the subgroup analyses of the phase III TORO trials for enfuvirtide, treatment responses were proportional to the number of genotype-sensitive drugs in the OBR.
Despite its higher rates of GI, hepatic and lipid adverse events, the drug is generally well tolerated. Tipranavir is “a welcome addition to currently available antiretroviral agents and represents an important option for patients with protease inhibitor-resistant viruses”.(42)
The entry inhibitors
In the spring of 2003, the first of a new class of treatments became available with the approval of enfuvirtide (T-20, Fuzeon). Enfuvirtide has a novel mechanism of action allowing for activity against virus resistant to the currently available medications. In addition, it is the first injectable ARV, and it was the first one FDA-approved specifically for patients with limited treatment options.(43)
In the HIV viral lifecycle, the entry inhibitors work to block HIV entry into the target cell, the first step in the viral lifecycle. There are currently three classes of entry inhibitors in development: those that target the CD4 receptor, those directed against the chemokine coreceptor and the fusion inhibitors exemplified by enfuvirtide. New drugs that target multiple sites in the viral lifecycle will obviously be welcome additions to our treatment arsenal and should lead to greater treatment successes. However, the continued availability of more and better ARVs in more and more classes at the same time make the treatment of HIV-infected patients increasingly complex.
Comprehensive reviews of enfuvirtide have been published elsewhere and will not be discussed here.(44,45) Although enfuvirtide is clearly efficacious in patients with very advanced disease having no other viable treatment options, several post-hoc analyses have afforded more insight into the optimal use of this agent.
Montaner et al(46) suggested that the best immunological and virological responses occurred in those patients with less advanced disease and those less antiretroviral- experienced (ie, patients with baseline CD4 count >100 cells/ml and HIV RNA<100,000 co/ml, those whose antiretroviral history included the use of no more than 10 ARVs, and the use of at least two other drugs suggested to be active by resistance testing). Responses were particularly good when patients were susceptible to lopinavir, which was part of the optimised background therapy.(47) Recently, additional analyses have clearly demonstrated the long-term efficacy of enfuvirtide (up to 96 weeks) and that the longer one waited to use enfuvirtide as part of cART, the poorer the responses would be.(48) As a result, some guidelines have suggested that “enfuvirtide is best considered at the time of the second, third, or fourth failure, depending on the number of active drugs that remain as options”.(49)
The past few years have seen a significant increase in the availability of new antiretroviral medications, as well as the addition of two one-pill once-daily combination medications. Treatment options for ARV-naive patients and, to a lesser extent, treatment-experienced patients, have been expanded. The approval of the first of the entry inhibitors, enfuvirtide, has been especially encouraging for highly treatment-experienced patients. Development of other entry inhibitors will add yet more treatment options, especially for treatment-experienced patients. Nevertheless, agents that work against highly resistant virus are sorely needed. The recently approved PI tipranavir holds hope in this regard, and the spectacular early results of the new PI TMC-114 are especially encouraging.(50) Finally, the long-awaited first results of an integrase inhibitor in HIV-infected patients, presented at this year’s CROI,(51) suggest that multiple targets against HIV are fast becoming a reality.