Approved agents

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A. Nucleoside reverse transcriptase inhibitors (NRTIs)

Azidothymidine (AZT, retrovir), was the first drug to show clinical efficacy and receive FDA approval. Its licensure is for first-line therapy in early- and late-stage adults and in children over 3 months of age. The 1997 DHHS guidelines recommend its use with ddl, ddC or 3TC as the two nucleoside components of a three or more drug HAART regimen. AZT is a thymidine analogue in which the 3'OH is replaced by an azido group. AZT is phosphorylated in HIV-infected cells to AZT triphosphate and is preferentially incorporated instead of the natural thymidine triphosphate into replicating viral DNA by the HIV reverse transcriptase, resulting in chain termination. Thus, it inhibits reverse transcription at two levels, substrate specificity and elongation, with selectivity resulting from its low level of utilization by cellular DNA polymerase a. The first placebo-controlled study done with AZT in patients with advanced AIDS indicated that AZT therapy might prolong survival. Therapy has also been shown to reduce the number of opportunistic infections. The primary side effect is bone marrow toxicity, but it can also cause myopathy and gastrointestinal distress. Like the other nucleoside analogues, it is orally bioavailable and is excreted renally. AZT given during the last two trimesters of pregnancy and to the newborn after birth has been shown to prevent maternal to fetal transmission of HIV. The emergence of AZT-resistant virus is associated both with duration of therapy and stage of disease, and detailed characterization of HIV mutations is well documented. With the demonstration of the therapeutic potential of AZT, other dideoxynucleosides were also investigated for therapeutic potential and resulted in additional licensures.

ddC (Hivid, Zalcitabine): like AZT, ddC is converted to the active antiviral agent ddCTP by cellular kinases and incorporated by the HIV RT into proviral DNA as a chain terminator, in place of dCTP. Unfortunately, ddCTP is also a substrate for cellular polymerase /? and mitochondrial polymerase y. The latter may be responsible for its primary toxicities, peripheral neuropathy occurring in about 25% of treated patients and pancreatitis in about 1% of treated patients. ddC is orally bioavailable and is excreted through the kidneys. Resistant mutants are often cross-resistant to ddl, d4T and 3TC. ddC is recommended in the 1997 DHHS Guidelines as a possible choice in combination with AZT for the two nucleosides in combination with a PI in HAART, but because of overlapping toxicities, ddC should not be used with ddl or d4T. The indication for which ddC was approved is as a combined therapy with AZT for patients with advanced AIDS.

ddl (Videx, didanosine): although extra steps are required for addition of the amino group to convert the inosine to adenosine, like the other nucleoside analogues ddl is processed by cellular kinases to produce the active antiviral agent, ddATP. The triphosphate competes with dATP for incorporation by the HIV RT into proviral DNA and results in chain termination. The intracellular half-life of ddATP is approximately 25 h, which is significantly longer than those of AZTTP and ddCTP. This suggests that it may be possible to decrease the number of daily doses needed from two to one. Didanosine is less orally bioavailable than the other nucleoside RTIs and must be taken on an empty stomach. Like ddC the principal toxicities are pancreatitis and peripheral neuropathy. The original approval was for adults who had already had long-term treatment with AZT and for treatment of adults or children who do not tolerate AZT or whose immune status deteriorated while on AZT. In the 1997 DHHS guidelines, ddl is recommended together with either AZT or d4T as a possible nucleoside combination to be used with a protease inhibitor as part of HAART.

d4T (Stavudine, Zerit) received approval for the treatment of patients who have failed to tolerate other approved therapies and for those who continue to decline on approved therapies. The 1997 guidelines list d4T, in combination with either ddl or ddC, as possible selection for the two nucleoside components of a triple drug regimen of HAART. Like the other nucleoside RTIs, d4T is phosphorylated to the active antiviral agent, stavudine triphosphate. Inhibition again is at two stages. First it competes with the correct RT substrate TTP and then further interferes by causing chain termination following incorporation. The three phosphorylation steps are all efficiently accomplished and there is not the accumulation of excess monophosphate with d4T that is seen with AZT. The primary toxicity is peripheral neuropathy.

3TC (Epivir, lamivudine, (—)-3'thiacytidine) received accelerated approval for use in combination with AZT on the basis of clinical trials using viral load and CD4 surrogate markers. Full approval was awarded in 1997 after improved survival was documented in an international study. Although 3TC is a potent inhibitor of both HIV and HBV RTs, resistant mutants are readily selected. Consequently it should always be used as part of a combination therapy. Its mechanism of action is similar to the other nucleoside analogues, e.g. phosphorylation to the triphosphate which is a competitive inhibitor of the HIV RT, with termination of growing proviral DNA chains. 3TC reacts less than the other nucleosides with the mitochondrial polymerase y, a feature which is presumably responsible for its more attractive safety profile. The 1997 DHHS guidelines for HAART recommend its use as one of two nucleosides, preferably with AZT, combined with a PI.

B. Nonnucleoside reverse transcriptase inhibitors (NNRTIs)

The NNRTIs differ from the NRTIs in that they do not have a nucleoside structure and do not depend on phosphorylation for activity. They function as noncompetitive substrate analogues and are selective inhibitors of HIV-1, with no activity against HIV-2 strains or even HIV-1 type O. Both approved NNRTIs have oral bioavailabilities greater than 60% and are highly protein bound. NNRTIs have been identified in multiple chemical classes, yet they all appear to bind the same region of the RT. This is separate from the binding region of the NRTIs, so the NNRTIs generally retain activity against AZT-resistant HIV variants. Although NNRTIs usually have potent antiretroviral activity, resistant mutants are readily selected and therefore these drugs are not recommended as monotherapy. The 1997 DHHS guidelines list the use of a combination of one NNRTI and two NRTIs as less preferred than a triple therapy of two NRTIs and a one PI.

Nevirapine (Bl-RG-587, Viramune) in early clinical trials dramatically illustrated both the ease with which treatment with this class of compounds results in the selection of resistant mutants and the efficacy of combination therapy in preventing their appearance. One trial compared monotherapy with nevirapine to its use in combination with AZT. There was a quick drop in serum p24 levels in both groups, but the monotherapy arm returned to baseline levels within a few weeks. The combination group sustained the decreased p24 levels. Nevirapine is generally safe, but a pruritic rash, which can usually be managed by dose reduction, is potentially severe and may be life threatening.

Delavirdine (Rescriptor, U901S2, a bis(heteroaryl)-piperazine) treated patients who received the drug as a monotherapy developed resistant virus within weeks of treatment. Accordingly, its approval is as part of a combination of antiretroviral agents and is based on surrogate markers rather than demonstrated clinical benefit. As with nevirapine, the primary toxicity is a rash which usually resolves, but can be serious.

C. Protease inhibitors (Pis)

The HIV protease is essential for the cleavage of the HIV polyprotein into the separate HIV proteins needed for virion assembly. The Pis are all highly potent enzyme inhibitors in vitro, and treatment with the first four Pis which were approved by the FDA have all resulted in improved CD4 cell counts and decreased viral loads. Improved clinical endpoints were also documented for the first three: Indinavir, Ritonavir and Invirase. Studies to determine the possibility of clinical benefit are underway for the fourth, Nelfinavir. These are the first drugs which attacked a viral target other than the RT and thus made highly potent combination therapies possible. In general, the pharmacokinetic properties of these drugs require strict observance of the dosing schedule to maintain efficacy and avoid the emergence of resistance. The Pis are principally metabolized by the liver cytochrome P450 oxidase system and consequently they can have serious interactions with other drugs in several classes. The Pis have been associated with a varied constellation of side effects which include the development of fatty masses, hyperglycemia and elevated triglycerides. New and exacerbated diabetes has also been reported during the postmarketing period, but it is not clear if this association is real or coincidental.

All four approved Pis are uncleaveable mimics of the HIV gag-pol polyproteins which occupy the active site of the protease. The inhibitors do not prevent the formation of progeny virions, but these virions are not mature and are noninfectious. Mutations which lead to resistance are usually (but not always) located in the drug-binding pocket and may require an accumulation of three or more for the development of significant resistance. Mutants resistant to one of these inhibitors often, but not always, show decreased sensitivity to other members of this class.

Inverase (saquinavir) has relatively poor oral bioavailability (about 5%) and has been formulated to maximize uptake and maintain plasma concentrations. It is metabolized by the liver P450 oxidase system, necessitating multiple dosing per day to maintain efficacy. Inverase's approval was based on both improvements in surrogate markers and a decline in disease progression and mortality in patients who received a combination of HIVID (ddC) and Inverase, as compared with patients who received either drug as a monotherapy. Safety for pediatric use has not been established. In 1997, Fortovase, a soft gel formulation of saquinavir which has significantly improved bioavailability, was approved.

Ritonavir (Norvir) is by contrast to Inverase much more readily orally bioavailable, requiring less frequent dosing. It is approved for use as a monotherapy or in combination with NRTIs on the basis of both improvements in surrogate markers of clinical progression as well as reductions in actual events of progression and mortality. Oral dosing is twice daily and a pediatric formulation is available for children aged 2 years or older. Interestingly, ritonavir enhances the plasma levels of saquinavir by up to 20-fold by blocking liver metabolism of the latter. This has the potential to provide a strategy to overcome the disadvantage of low bioavailability of saquinavir, but the predictability of the magnitude of this effect is not reliable and would necessitate extensive monitoring of patients receiving both drugs in combination.

Indinavir (Crixivan) obtained accelerated FDA approval with the demonstration of undetectable plasma virus load and increased CD4 cell levels when given in combination with two nucleoside analogue RTIs or as a monotherapy. It is not approved for pediatric use. To maintain adequate serum levels, Crixivan must be taken at 8 h intervals.

Nelfinavir (Viracept) is the most recently approved drug in this class and approval was based on changes in surrogate markers when it was administered either as a monotherapy or in combination with NRTIs. It is dosed orally three times a day and a pediatric formulation is available. A preliminary study suggested that some nelfinavir-resistant mutants may retain sensitivity to some other Pis, although nelfinavir was not always inhibitory to HIV mutants resistant to other Pis.

Experimental agents

New nucleoside (Lodenosine) and nucleotide (Adefo-vir dipivoxil) analogue RTIs and NNRTIs (Efavirenz) are in various stages of preclinical and clinical development, with the hope of achieving high plasma levels, overcoming resistance development, and also providing added benefit in combination with approved agents.

Also a new generation of protease inhibitors is in development, with the aim of providing greater efficacy in combination with Pis and RTIs (Ampre-navir, 141W94), improved oral bioavailability (DMP-

450) and efficacy against virus resistant to other Pis through novel binding to the protease active site (PNU140 690; BMS 232 632; PD 178 390).

Numerous novel approaches against virtually every stage of the viral replication cycle are being pursued, and will just be mentioned in passing. These include the use of oligonucleotides (GEM 92; Zintevir; ISIS 5320) to inhibit by a combination of methods, potentially including antisense-mediated inhibition of RNA translation, blockade of virus adsorption and/or blockade of HIV provirus integration. A receptor-binding antagonist, RBC-CD4, uses the strategy of coating erythrocytes with surface CD4. These cells internalize free HIV, thereby preventing new infections, and also bind to gpl20 on infected lymphocytes, resulting in phagocytosis of already infected cells. Peptide and/or nucleotide decoys which will interfere with the binding of the HIV TAT regulatory protein with the targeted TAR region of the HIV genome are also being investigated. Zinc fingers, which are highly conserved regions of HIV proteins that bind to the packaging region of the HIV genome RNA, are attractive targets as they are involved in multiple stages of the replication cycle including reverse transcription, genome integration, RNA packaging and protease function. Inhibition of multiple zinc finger functions make it theoretically likely that resistant viruses will not emerge. In addition, since they are part of the virus structure, drugs directed at zinc fingers may also be virucidal.

In addition to strictly antiviral approaches, several other strategies deserve mention. Multiple cellular functions have been targeted, including modulation of the immune system. The combination of HAART with interleukin 2 (1L-2), to stimulate CD4 T cells and enhance resistance to secondary infections in AIDS, is in clinical evaluation. The therapeutic use of killed vaccines is also in clinical trials as a means of boosting residual immune function. Other cellularly targeted agents include hydroxyurea (HU), which blocks cellular ribonucleotide reductase and depletes nucleotide pools for nucleic acid synthesis. The enhanced DNA incorporation of nucleotides derived from antiviral nucleosides is hypothesized to explain the potentiation of ddl's activity by HU when they are used in combination. Resistance is not a problem as the HU target is cellular.

Two approaches involving genetic alteration of the patient's stem cells are intriguing, although their practical utility remains to be demonstrated. The first, in phase I/II clinical trials, involves the transduction of HIV-targeted ribozymes into stem cells by means of retroviral vectors. Ribozymes are RNA enzymes which cleave at a specific HIV RNA nucleotide sequence following complementary base pairing.

The second approach involves transfecting lymphocytes and stem cells ex vivo with genes encoding intrakines such as CDF, Rantes or MlP-la. These serve to block the surface expression of both HIV coreceptors (CXCR4 and CCR5) and protect the intrakine-expressing cells from infection.

A possibly more feasible 'Trojan horse' strategy also is based on the use of cellular receptors for HIV. With this strategy, the envelope gene of vesicular stomatitis virus (VSV) is replaced with the genes encoding the T cell receptors (CD4 and CXCR4) for HIV. HIV-infected cells, displaying gpl20 on their surface, now can fuse with the T cell decoy and are killed by the cytolytic virus. Similar decoy constructs are being developed to mimic macrophages. Although VSV is normally a mild pathogen for cows and pigs, and even milder for the accidentally infected humans, the decoy is noninfectious for these species owing to the loss of its envelope protein. The decoy can only infect and replicate in HIV-infected cells. The strategy has only been evaluated in tissue culture, but the clinical potential is exciting.

These myriad approaches underway inspire confidence that new therapeutic strategies will enable successful control of HIV, with the clear goal of providing drugs and strategies that will effect cures at costs that do not preclude their use.

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