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New antiretroviral agents and the complexity of treatment practices: If you don't know what N155H means then you shouldn't be treating HIV-infected patients.


Ongoing advances in new drug development and clinical trials have brought a number of new drugs and new drug classes to the clinic. The arrival of these agents has the potential to fundamentally change the way we achieve control of HIV replication, as well as adding further complexity to prescribing practices.

HIV treatment has come a long way since zidovudine was first licensed in the 1980s. Despite one of the most dramatic reductions in short-term mortality seen in an HIV clinical trial, the effects were not sustained and the initial dose used was too high [1]. Many of the advances in HIV treatment were slow, such as the realisation that more than one or two drugs were needed to durably suppress the virus. Many of our prescribing practices were based simply on the time lines by which new drugs were available for use in clinical trials. As such, regimens of two nucleoside analogue reverse transcriptase inhibitors (NRTI) plus either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) have been, and still remain the recommended treatment choices.

With the arrival of new drug classes this practice is now ready for a change. Not only are there increasingly effective options for treatment-experienced patients, but there is now the possibility of using the treatment armamentarium in a completely different manner, mainly to avoid some of the toxicities that are part of current treatment. As experience grows so do improvements in care:

* Fewer blood transfusions are necessary as we have stopped using high-dose zidovudine in late-stage patients;

* We see less peripheral neuropathy as fewer patients are on combinations involving didanosine and stavudine [2];

* We see less lipodystrophy as stavudine usage reduces;

* We see fewer renal calculi and dry skin as indinavir usage reduces.

Despite dramatic improvements in morbidity and mortality, all is not perfect with current treatment. We still see increasing lipid abnormalities as our patients age on treatment. We are still concerned about longer-term issues such as renal impairment and reductions in bone density with older patients. Many of these problems are related to the mitochondrial DNA polymerase inhibition effects of the NRTIs or the metabolic effects of ritonavir-based PIs [3]. Attempts at class-sparing combinations, mainly to avoid NRTIs have had some limited success but do not seem to get around the problems of tolerability with the alternative regimen. For example the recently published ACTG 5142 study found a slightly reduced viral suppression rate with an NRTI-sparing combination of a PI plus efavirenz but significantly more adverse events [4].


The arrival of this class of agents provides an opportunity to juggle our backbone agents in different ways. Grant and Zolopa have written an extensive review of the properties of integrase inhibitors in their article. To date, the efficacy results have been impressive, with more rapid reductions in plasma viral loads than seen with standard therapies [5]. The toxicity profile is also appealing: no apparent mitochondrial effects; no metabolic effects; and no lipid increases. Their Achilles' heel would be the ease of development of resistance mutations, with only a single point mutation required to render them ineffective. However, this has not been an issue for similar drugs, such as the NNRTIs. Proper patient selection should see these drugs being utilised earlier in the treatment continuum. Currently their use is reserved for heavily treatment-experienced and drug-resistant patients for whom there are few additional potent agents to couple with the integrase inhibitor. With raltegravir having a twice-daily dosing schedule and elvitegravir being once daily, but with ritonavir boosting, it will be interesting to see what predicts greater usage.


Blocking the cellular target CCR5 has a conceptual appeal, as patients defective in this receptor are more likely to be long-term non-progressors and it does not suffer from the plasticity seen in HIV enzyme targets [6]. Both maraviroc and vicriviroc have shown effectiveness as salvage therapies in treatment-experienced patients, with maraviroc already licensed in many countries. Unfortunately, CCR5 is not the only entry receptor for HIV, with CXCR4 or dual tropic virus able to infect cells coated with CCR5 inhibitors [7]. Pre-screening patients for viral tropism is therefore a necessary but cumbersome step in initiating this drug. The test is, however, not very sensitive, with recent data suggesting mixed tropism if more sensitive technology is used. Once experience with these drugs develops, it is likely that various 'nuc'-sparing combinations that incorporate an entry inhibitor will start to become popular.


Still just coming over the horizon are the Gag maturation inhibitors. They are still early in drug development and it is not yet clear whether they will make it to the clinic. However, early data looks promising. Dosing schedules and resistance patterns still need to be defined. Again, as they are members of a new class of drugs, their appeal will initially be for use in experienced patients.


Both darunavir and tipranavir have shown potency in PI-experienced patients as they have differing mutation patterns from earlier PIs and a higher genetic barrier to resistance. Although initially studied in heavily treatment-experienced patients, more recent studies, such as TITAN, actually found superiority of darunavir over lopinavir, in less experienced patients. Only the potential spectre of hepatotoxicity that haunts so many drugs has been reported with both of these agents. However, this and other inflammatory problems seen with the use of darunavir in advanced patients may be more related to greater immune reconstitution than true drug toxicity. As highlighted by Lascar and Cartledge, it is difficult to precisely determine any relative differences in efficacy between these two drugs, based on the different clinical trials conducted, the allowable background regimens and the level of treatment experience in each. The uptake of these agents may depend more on drug interaction concerns than efficacy differences; for example, the DUET trials showed that the majority of treatment-experienced patients were able to suppress viral replication when darunavir was used with etravirine as salvage therapy. However, tipranavir interacts with etravirine and they are not recommended for use together.


While the NNRTIs have been a mainstay of therapy for many years, each of the currently used drugs has toxicity concerns: rash and hepatotoxicity for nevirapine and CNS effects for efavirenz. In addition, while the majority of patients is able to continue NNRTI-based therapy, for a significant number, and particularly naive patients considering treatment options, these toxicities are unwanted. Etravirine, in its limited usage, seems to have a relatively clean toxicity profile, as well as working against virus that carries key NNRTI mutations. It will be interesting to see whether etravirine creeps into earlier, possibly naive patient use or remains reserved for salvage therapy. Of interest on the horizon is the next generation of NNRTIs, which also bring the promise of efficacy against resistant strains as well as once-daily dosing; as detailed by Pozniak in this issue.


HIV management has always been a rapidly changing field, as new information from numerous clinical trials updates us with what is good and not so good about different treatment options. Understanding how to get the majority of our patients adequately suppressed on treatment, with minimal toxicity for the next 10-20 years requires an understanding of a range of issues: differential drug efficacy, individual drug toxicity, interactions, compliance issues and resistance patterns. N155H is a key resistance mutation for the integrase inhibitors. Understanding this requires knowledge of all these other factors as well.


(1.) Fischl MA, Richman D D, Grieco MH et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med, 1987, 317, 185-191.

(2.) Moore RD, Wong WM, Keruly JC, McArthur JC. Incidence of neuropathy in HIV-infected patients on monotherapy versus those on combination therapy with didanosine, stavudine and hydroxyurea. AIDS, 2000, 14, 273-278.

(3.) 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 antiretroviral-therapy-related lipodystrophy. Lancet, 1999, 354, 1112-1115.

(4.) Riddler SA, Haubrich R, DiRienzo AG et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med, 2008, 358, 2095-2106.

(5.) Markowitz M, Nguyen BY, Gotuzzo E et al. Rapid and durable antiretroviral effect of the HIV-1 integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr, 2007, 46, 125-133.

(6.) Stewart GJ, Ashton LJ, Biti RA et al. Increased frequency of CCR-5 delta 32 heterozygotes among long-term non-progressors with HIV-1 infection. The Australian Long-Term Non-Progressor Study Group. AIDS, 1997, 11, 1833-1838.

(7.) Nolan KM, Jordan AP, Hoxie JA. Effects of partial deletions within the human immunodeficiency virus type 1 V3 loop on coreceptor tropism and sensitivity to entry inhibitors. J Virol, 2008, 82, 664-673.

Correspondence to: Dr Don Smith, Director of Clinical Services, Albion Street Centre, Sydney, Australia.

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Article Details
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Author:Smith, Don
Publication:Journal of HIV Therapy
Article Type:Editorial
Geographic Code:8AUST
Date:Jun 1, 2008
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