A review of new anti-HIV drugs in development

Graeme Moyle, MD

The 5th International Congress on Drug Therapy in HIV Infection in Glasgow, Scotland commenced with several keynote lectures discussing emerging treatment strategies for people with HIV infection. Professor Michael Saag from the University of Alabama at Birmingham, USA, provided the first of these discussions, which was an overview of drugs in development.

He provided us with a potpourri of drugs, predominantly in current clinical development for which activity in humans had been demonstrated. This included drugs from the nucleoside analogue reverse transcriptase inhibitor (NRTI), nucleotide analogue (NtRTI), non-nucleoside reverse transcriptase inhibitor (nNRTI), and protease inhibitor (PI) drug classes, as well as a discussion of the novel agents in development such as fusion and entry inhibitors. Dr. Saag also briefly touched on the identification of candidate agents such as integrase inhibitors. Drugs from this class have not yet entered clinical development, although candidate agents have been identified.

Nucleoside Analogue Reverse Transcriptase Inhibitors (NRTIs)

With regard to nucleoside analogues, Dr. Saag discussed two agents in advanced development in this area, although he also pointed out that new formulations of established drugs, such as enteric coated (EC) ddI (didanosine, Videx), the combination tablet of ZDV/3TC/ABC (Trizivir) and a slow release formulation of d4T (stavudine, Zerit), are also either approved or in clinical development.


Regarding new nucleoside analogues, these include DAPD, an agent which is converted in vivo into dioxalone guanasine (DXG), which is then activated to a triphosphate form, as for other nucleoside analogues. This drug has show 1-1.5 log reductions in viral load as a monotherapy over fifteen days in treatment-naive patients. This agent also demonstrates in vitro activity against a range of viruses which are resistant to current nucleoside analogues.

Emtricitabine (FTC, Coviracil)

The second nucleoside analogue in advanced clinical development is emtricitabine (FTC, Coviracil). This nucleoside analogue is similar to 3TC (lamivudine; Epivir) in its structure and, like 3TC, has activity against both HIV-1 and HIV-2 and hepatitis B virus (HBV). FTC has an advantageous long half-life, which enables once daily dosing. As with 3TC, the key mutation with FTC is the 184V mutation. Studies in monotherapy over fifteen days with FTC indicate 1.5-2 log drops at a 200 mg qd dose. The French ‘Montana’ Study recently reported by J. P. Molina at the 40th ICAAC meeting in Toronto (September 17-20, 2000), indicated that a once-a-day regimen including FTC with ddI and efavirenz resulted in 93% of patients by intention-to-treat analysis had achieved a viral load of less than 50 copies per millilitre (mL)by week 24.


Dr Saag then moved on to discuss tenofovir, a nucleotide agent in advanced development for HIV infection. A relative of tenofovir, adefovir dipivoxil, was recently discontinued for anti-HIV indication due to limited antiretroviral efficacy and problems with renal [kidney] toxicity. This was shown to be related to the accumulation in renal-tubular cells of adefovir, secondary to a transporter mechanism involving human organic anion transporter (hOAT) type 1.

Tenofovir has not thus far been reported to be associated with renal toxicity, possibly because it is not a substrate for this transporter molecule. It appears to be suitable for once daily dosing and retains activity in a number of resistance backgrounds. The 3TC/FTC resistance conferring 184V mutation appears to increase the sensitivity of the virus to tenofovir treatment, and tenofovir appears to maintain activity in the presence of 215-complex nucleoside analogue mutations (NAMs) as well as the multi-drug resistant Q151M mutation in vitro. However, attenuation has been observed in the activity of tenofovir in the presence of the rare 69SSS insertion mutation in combination with NAMs.

A clinical study evaluating intensification of therapy with tenofovir in nucleoside analogue-experienced patients, indicated that 300 mg once daily achieved a mean reduction in viral load of 0.7 log with similar effects being observed in individuals who were ZDV- resistant had the 184V mutation associated with 3TC resistance and had nNRTI or PI resistance. In this study a significant rise in CD4 count was not observed, however. Dr Saag suggested that this may relate to the fact that these individuals were already at least partial responders to antiretroviral therapy and may therefore have already achieved a CD4 count response which was not further affected by the modest additional reduction in viral load that followed tenofovir inclusion in the regimen.

Non-Nucleoside Reverse Transcriptase Inhibitors (nNRTIs)

MKC 442 (Coactinon)

Dr Saag then turned to the non-nucleoside (nNRTI) drug class. Several agents in this class are in clinical development, including emivirine (MKC 442, Coactinon), which is in fact a nucleoside analogue drug but with nNRTI type activity. Monotherapy studies with this drug at 750 mg bid have indicated a maximal viral load response of 1.5 log over fifteen days. At week 48, combination triple therapy, including MKC 442 plus 2 nucleoside analogues in treatment of naive patients found a reduction in viral load to less than 50 copies in 30-42% of patients treated. These results were somewhat disappointing and have delayed the approval of MKC 442. Further studies are now ongoing evaluating the efficacy of MKC 442, to see whether it can match up to the responses observed with other non-nucleoside agents.

AG-1594 (Capavirine)

Other drugs in the non-nucleoside class which are in clinical development are of interest because of either improvements in pharmacology or because of the potential for activity against viruses which have at least a single mutation conferring resistance to the currently available non-nucleoside drugs. One of these drugs includes Capavirine (AG-1594), which is likely to be dosed at 2,100 mg (3 tablets) twice daily, with dosing required to be in a fed state. Over 10 days monotherapy of this drug has been associated with a response of 1.6 to 1.8 log reduction, and in vitro it appears to carry activity against the K103N non-nucleoside resistance-conferring mutation.

DPC 083

DuPont Pharmaceuticals is involved in the development of a number of candidate compounds from the quinazolinone which include DPC 961, 963, 082 and 083. These drugs appear to be active, or at least show only modest attenuation of activity in the presence of single mutations associated with resistance to current nNRTI’s although dual mutations such as 103N + 100I still appear to be a problem. Several of these drugs have very prolonged half-lives, suggesting once daily or less dosing, and their protein binding, although high, is lower than that reported from efavirenz. For example, the DPC 083 candidate compound has protein binding of 98% compared with efavirenz, where protein binding is in the range of 99.5% or more. This suggests that these compounds will have more free drug available for achieving an antiretroviral effect and, therefore, an achievement of higher trough-free drug values to inhibitory concentrations (inhibitory quotions) may be achieved.

Protease Inhibitors (PIs)

Lopinavir/Ritonavir (Kaletra)

When discussing protease inhibitors, Professor Saag mentioned the recent approval in the USA and the availability on expanded access program in much of Europe of Kaletra (lopinavir/ritonavir; ABT-378) combination tablets [from Abbott Laboratories], and that this formulation has demonstrated superiority in a BID regimen to a three times daily nelfinavir-based regimen. However, at the present time, it is unclear whether this drug should be used as a first line [initial therapy] PI choice, or whether it should be saved for PI salvage, where it is also demonstrated to have potent antiviral activity in combination with other nucleoside and non-nucleoside drugs.


Other drugs from the protease inhibitor class of interest at the present time include tipranavir [from Boerhringer Ingelheim], which is the first non-peptidic protease inhibitor in clinical development. This drug has demonstrated activity in a dose ranging study. However, it has relatively unfavourable pharmacokinetics, and therefore is likely to require the inclusion of ritonavir in the regimen to achieve a boosted exposure of tipranavir. This drug is now entering Phase 2 studies.

BMS 232632

BMS 232632 [from Bristol-Myers Squibb] is a peptitic protease of similar design to those that are currently available. However, this drug appears to have more favourable pharmacokinetics, which enable once-daily dosing to be achieved. Dosing is likely to be with food. A small dose finding comparative study has reported similar response with 2 nucleoside analogues for BMS 232632 and nelfinavir over 24-48 weeks of follow-up with approximately 60% of patients being undetectable at this time point by a <50 copy assay.

The main side-effect associated with BMS 232632 has been an elevation of indirect bilirubin, the mechanism of which relates to an inherited genetic variation in the population and was recently described by O’Mara et al at the 40th ICAAC meeting in Toronto (September 17-20, 2000). One important consideration with BMS 232632 from the first study is that it does not appear to be associated with significant cholesterol or triglyceride elevation during use.

DMP 450

Other drugs that have show activity in the protease class include DMP-450, a cyclic urea protease inhibitor with a half-life of 9 hours, enabling twice daily dosing. A small 48-week study in combination with nucleoside analogues in treatment-naive individuals has indicated a fall in viral load of 2.5 to 3 logs, with 60% or more individuals being <50 copies/mL at week 48 by intention-to-treat analysis.

DPC 681, 684 and AG 1776

Other protease inhibitors in development include two DuPont compounds, DPC 681 and 684, which show limited attenuation of activity in the presence of virus resistance to current protease inhibitors. For example, a multi-PI-resistant mutant containing five mutations at codons 82F, 84V, 71V, 46I and 63P showed a less than six-fold shift in phenotypic sensitivity to these agents. However, Dr Saag also indicated that at least one drug, AG 1776, had recently been discontinued from development. However, Agouron Pharmaceuticals is pursuing analogues of this original compound to see whether improvements can be made to the pharmacology, safety and efficacy of this particular member of the protease inhibitor drug family.

HIV Fusion and Entry Inhibitors

Although there is considerable need and interest in drugs from available drug classes, particularly if those drugs have activity against virus resistant to currently available drugs, there also remains a substantial need for the availability of new and novel agents, which take different sites involved the virus life cycle. The area of most interest at the present time is in drugs that interfere which attachment, fusion or entry of HIV into infectable cells.

The process of attachment may be affected by new versions of soluble CD4 which are under investigation in vitro and by agents that inhibit either CXCR4 or CCR5. The chemokine receptors are key to triggering a confirmational change in the viral surface glycoprotein, Gp41 which leads to subsequent fusion of virus with human cell. Once Gp41 attaches to a chemokine receptor it undergoes a confirmational change in which something akin to harpoon or spear is fired into the surface of the cell to which the virus is attached. This harpoon has both a C and N terminal, which folds together into a hairpin shape drawing the virus adjacent to the surface of the human cell, enabling fusion to occur.

T-20 and T-1249

Several peptitic compounds, such as those from Trimeris Pharmaceuticals and Roche Laboratories, T-20 and T-1249, are known to attach to the N-Terminal of the hairpin and block the completion of hairpin formation and therefore preventing the drawing near of the virus to the human cell and preventing fusion occurring. Dose ranging studies with T-20 indicated that a dose of 100 mg /12 hours led to reductions in viral load of approximately 1.5 log over 18 days. Prolonged follow-up to week 48 in a single arm study in combination with a salvage regimen of a genotypically directed selection of antiretroviral agents has indicated sustained 1-1.5 log across this population, which was predominately in individuals with virus resistant to all available drug classes.

The drawback of these peptidic fusion inhibitor compounds is that they require subcutaneous injection, although new formulations are leading to improved tolerability of these injections, enabling relatively easy and acceptable twice-daily administration. Given that these agents are peptitic compounds and administered subcutaneously, they are unlikely to have significant drug interactions with the currently available antiretroviral drugs. The final subject that Dr. Saag discussed was the potential for immunotherapy, specifically whether we can learn from long-term non-progressor patients. Many of these individuals have significant anti-HIV cytotoxic CD8 lymphocyte response and persistence of activated HIV specific CD4 helper lymphocytes, and it is hoped to reproduce these HIV-controlling responses in a higher proportion of patients. Several approaches are examining this strategy. These include forms of antigenic stimulation, such as with a range of vaccine based treatments, use of structured treatment interruptions as will be discussed in another section of this report, or in the use of natural immuno-modulators, such as interleukin-2 to mobilise CD4 cells and enhance the activity of CD8 cells.


Dr Saag closed by suggesting that the themes for therapy over the next few years with the availability of new drugs and the currently available classes is going to focus on achieving similar or better potency to what we are achieving with current antiretroviral regimens, but with improved convenience and tolerability, which will make these combination therapies more readily tolerated in the long term for individuals with HIV infection.

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