8th Annual Retrovirus Conference
Opening Session
Chicago, Feb 4-8 2001

Report 3

New agents promise tempered with caution on side effects, pharmacology and resistance: Antiviral Chemotherapy session 1
     Written for NATAP by Graeme Moyle MD, MBBS. Chelsea and Westminster Hospital London UK

The antiviral chemotherapy 1 session today at the 8th Annual Retrovirus Conference unveiled several new agents from both new and established drug classes which hold promise for both the ësalvageí setting and treatment simplification. However, questions remain as to whether these agents will deliver in terms of pharmacology, their efficacy against strains of virus resistant to current agents and whether side effects will be fewer. Additionally, this session and others at the conference suggest a shift in interest towards immune based therapies as additional components of HIV therapy. This shift, lead by interest in both immune modulators like interleukin-2 (IL-2) and vaccine approaches, perhaps marks a watershed. Whilst in the 1980s the key marker used in managing HIV was the absolute CD4 cell count, whereas in the ë90s the treatment mantra was the patronizing squeal from virologists of ëItís the virus, stupidí. In the ënoughtyísí we may be seeing a more balanced approach; making the CD4 count go up and viral load go down is not enough, restoring the immune system rapidly, and in a way that it can better manage HIV without the need for sustained drug therapy, could be the achievement for this decade.

A clutch of new NNRTIs and PIs are reporting data, mostly pre-clinical or early clinical, at this meeting. The main issue for drug developers in both NNRTI and PI classes is the extent of cross-resistance that exist between the available agents of these classes, such that when resistance to one agent has developed it can render an entire class of inhibitors ineffective. Two approaches may be used to manage this problems: using boosted drug levels (particularly trough levels) to overcome low level shifts in sensitivity (such as with the PIs Kaletra or baby-dose ritonavir with saquinavir, indinavir or amprenavir) or to develop novel agents which do not exhibit cross-resistance to current agents (such as the PI Tipranavir or possibly the NNRTIs capavirine and DPC-083). Ideally, new agents in these classes would possess both high potency against mutant variants of HIV and show higher levels of free drug throughout the dosing period.

 DPC 681 & DPC 684: for Protease Inhibitor Resistant Virus

 DuPont has already commenced efficacy trials with their so-called ësecond-generationí NNRTI DP-083 but also have a pipeline of ësecond-generationí  PIs in pre-clinical development which represent potential candidates for development in this class. Two agents DPC 681 and DPC 684 reported in vitro data which show promise in satisfying both these needs. The agents have a chemical design (substituted sulfonamides) which bears some resemblance to amprenavir and a highly potent compound from Searle discontinued in the early '90s because of pharmacokinetic issues. These new DPC compounds are potent inhibitors of HIV protease enzyme (Ki 10ó20 pM) with 90% inhibitory concentrations (IC90) for wild-type HIV-1 of 4-8 nM (similar to lopinavir and up to 10 times more potent than indinavir). Of note, similar potency was observed across non-clade-B viral isolates, the types of viruses most prevalent outside the US and Europe. As with currently available PIs, DPC 681 and DPC 684 showed no loss in potency against mutant virus with the D30N Nelfinavir mutation and maximal 5.6-fold loss in potency towards variants with up to 5 mutations. Greater than 4 fold shifts are often considered relevant to clinical resistance. Viruses derived from clinical samples from patients who have failed PI-containing regimens and containing 6 or 7 mutations including positions 10, 63, 71, 82, 84 and 90 showed a 3- to 6-fold loss in sensitivity to DPC 681 or DPC 684. In contrast, these mutant variants showed a 13-190 fold loss in sensitivity to available PIs. These drugs have high levels of binding to plasma proteins although the levels reported (98.1-98.4%) are similar to or better than some approved PIs. Thus, potent exposures of these agents should be achievable in humans. Following the successful completion of safety and pharmacology studies in animals, Phase I clinical studies in healthy volunteers, to help establish doses for testing in people with HIV, are now underway1.

 TMC126: high potency against highly resistant PI virus

 DuPont is not the only company with candidate agents in both NNRTI and PI classes. TIBOTEC, a drug development start-up with close links to the virology diagnostics company Virco, also presented data on two potentially exciting compounds. Their methodology, with the collaboration of scientists at the US National Institutes of Health (NIH), was to pursue a structure- and fitness-based strategy using computer-based drug design, in combination with drug resistance profiling, to discover PIs that possess not only high potency and activity against viral mutants resistant to current PIs but also a so-called ëresistance repellantí design. In this approach the drug retains the ability to limit or ësuppressí the evolution of drug resistant variants along genetic pathways commonly observed with approved Pis, but interacts with protease at highly conserved points which would lead to dramatic impact on viral fitness if mutated. The lead compound in their stable, called TMC126, shows previously unreported high levels of potency. When directly tested against the enzyme, the Kd of TMC126 against wild type protease was measured to be 0.38 x 10-15M. This and related drugs possess the ability to inhibit wild type and multi-drug resistant clinical isolates of HIV with IC50values as low as to 0.1 x 10-9M. The drug was also demonstrated to establish barriers to the emergence of common active site mutations through limiting enzyme fitness thus resulting in resistant strains emerging more slowly and along novel genetic pathways. Pharmacological properties of this agent were not described but TMC126 and several related compounds in this series are ëbeing evaluated for suitabilityí as candidates for clinical development with at least one agent having ëdecentí bioavailavility in dogs2.

 TMC120: for NNRTI resistant virus

 The second TIBOTEC compound discussed was a new NNRTI. This agent TMC120 (also called R147681), is from a chemical group called dianilinopyrimidine (DAPY) derivatives (i.e. it is distantly related to some previously discontinued NNRTIs but unrelated to approved agents).  Itís in vitro activity with an IC50= 1-10 nM against wild-type HIV-1 is similar to Efavirenz.  However, with this agent, activity against mutants resistant to approved NNRTIs (efavirenz, nevirapine and delavirdine) such as those with mutations  K103N, Y181C or G190A/S (single) mutations is not diminished. Modest, >5-fold shifts in sensitivity were seen with infrequently observed 100I and 188L mutations. This drug has now completed a first clinical evaluation and proceeding with further activity and safety studies. Ultimately, the best assessment of a drug's clinical potency is how well it works alone. However, as considerable ethical concerns exist regarding the risk of resistance development during monotherapy studies, only very short term assessments of agents as monotherapy is feasible. Seven-day studies, such as reported with TMC120, may underestimate the peak viral load drop provided with a drug but provide some meaningful assessment of drug activity. In particular, mathematical models are applied to the slope of decline in viral load over 7 days to provide an assesment of the rate of fall or ëdecayí in virus relative to data with established drugs. The reported study was a randomized, double-blind study comparing two doses of TMC120 (50 or 100 mg BID) as monotherapy  to placebo for 7 days in treatment-naive HIV-1 infected patients with viral loads between 5,000 -125,000 copies/ml). Triple therapy with approved antiretrovirals was offered thereafter. The study conducted in Russia and Poland involved 34 men and 9 women previously naÔve to therapy. The median baseline CD4 cell count was 571 cells/mm3 and viral load 40,258 copies/ml. Decay rates were -0.02 for the placebo (i.e. essentially no change in viral load) and  -0.213 for the 50 mg and -0.237 for the 100 mg group. In both cases these falls were significantly different to placebo in demonstrating potent antiviral activity. The 7-day changes in viral load  (log10copies/ml) by treatment group (placebo or TMC 50 and 100mg BID) were ñ0.17, -1.44 and ñ1.55, respectively. No resistance has been detected in samples at the end of therapy. Pharmacokinetic data suggested drug exposure at trough up to 50 times above protein corrected in vitro IC50. The TMC120 appeared well tolerated with 3 patients reporting possible drug-related adverse events; mild somnolence, or insomnia and one subject (on 50 mg BID) was withdrawing after day 4 because of an HIV related problem. As the antiviral effects of the two doses of TMC 120 were not significantly different further studies will be required to determine which dose will go forward to larger studies3.

 BMS-232632: new once-a-day dosed protease inhibitor

 The new protease inhibitor in most advanced development is Bristol Myers Squibbís BMS 232, 632. This agent is a potent PI with activity in vitro (IC502-5 nM, comparable to saquinavir), and a pharmacokinetic profile that supports once-daily dosing with a low tablet load.  Drug absorption is improved by food. Studies in persons with virus known to be resistant to approved PIs are required to establish whether the activity observed in vitro against some resistant strains is apparent in practice. The study reported here relates to a dose finding study in treatment naÔve patients with viral loads > 2000 copies/mL, preliminary data from which has been presented at previous meetings. This randomized study compares the safety and antiretroviral activity of 3 dose levels of BMS 232632 once daily with nelfinavir (NFV) 750 mg tid both as monotherapy for 2 weeks followed by the addition of didanosine (ddI) and stavudine (d4T). Of note, as both NFV and BMS 232623 are dosed with food and ddI is dosed on an empty stomach the regimens studied are relatively complicated. The study involved initially 92 subjects  (data through 48 weeks), and with a subsequent 166 patients added after satisfactory preliminary results (data through 24 weeks). Efficacy data at week 24 indicated 65-68% of BMS 232, 632 treated and 63% for nelfinavir treated patients were <400 copies/ml. CD4 cell count rises were similar across treatment groups. The most common possibly drug-related adverse events were diarrhea (17% for BMS 232, 632 vs. 51% NFV) and nausea (13% BMS 232623, 7% NFV). A raised bilirubin (usually without obvious jaundice or other symptoms and not associated with other abnormal liver function), was seen with BMS 232623 in 28% of patients at 400mg QD, and more often at 500mg, the highest tested dose. No significant elevations in cholesterol, LDL-cholesterol, or triglycerides were observed in the BMS arm, whereas in the NFV arm a sustained rise of 20-50 mg/dL was observed4. The practical relevance of this difference is unclear. This agent in now progressing to further studies in a range of clinical settings at the 400mg dose and in comparison to current standard of care regimens.

 FTC: new nucleoside

 There remains a need for new nucleoside analogue agents both because of concerns regarding the long-term toxicity of some agents in this class and the extent of cross-resistance that is increasingly appreciated between different members of this class. Potential candidates form the nucleoside and nucleotide classes include the nucleotide tenofovir (Gilead) and the nucleosides DAPD and FTC (both from Triangle Pharmaceuticals and Abbott). Data on FTC were presented during this session. FTC is a NRTI of similar chemical structure to 3TC but with in vitro potency against HIV which is 4-10 times greater than 3TC. It is suitable for once daily dosing but, as with 3TC, it selects for the M184V resistance mutation. As with 3TC, its is also active against Hepatitis B. An initial 2 week monotherapy study with FTC showed an approximately 2 log10median decrease in viral load at 200 mg once daily (QD). Data from two randomized, controlled equivalence trials of 150 mg 3TC BID compared with 200 mg FTC QD in triple therapy combination regimens were reported. In study FTC-303, 440 patients with viral loads <400 copies/mL) on a 3TC containing triple therapy regimen for >12 weeks were a randomized (2:1) in an open-label manner to switch to FTC or continue on 3TC. Eight% of the patients in each arm have experienced viral rebound above 400 copies/ml to date with no differences to week 48 observed between drugs and few drug related adverse events.  A second study, FTC-302 was a randomized, double blind study in 468 patients comparing FTC to 3TC plus stavudine and either nevirapine (NVP) (if screening viral load <100,000 copies/mL) or efavirenz (EFV) (if screening viral load >100,000 copies/mL) in treatment naÔve patients.  No differences in efficacy, as determined by the proportion of patients experiencing viral rebound has been reported but viral rebound occurred in 12% of FTC but 6% of 3TC patients (p<0.05). However, adherence may be the reason as 60% of rebounders on FTV (Vs. 23% on 3TC) had wild type virus  and only 15% had the 184V mutation compared to 54% of 3TC rebounders (p=0.03). Adverse events were predominantly mild to moderate in both groups. Of note, all 58 patients in this study who experienced grade 3 or grade 4 (moderate or severe) elevations in liver enzymes were in the NVP stratum (see below)5. These studies support equivalent antiviral activity and safety at once-daily FTC compared to twice daily 3TC in HIV-1 infected patients initiating therapy or switching from 3TC to FTC with HIV-1 RNA<400 copies/mL. However, given that pharmacokinetic and preliminary data for previous and on-going studies suggest that 3TC may also be given once daily, and that adverse vents clearly related to 3TC are rare, the place of FTC in the therapeutic armamentarium remains obscure. (An abstract at this Conference reports on patients successfully switching to 3TC once-daily after being undetectable on 3TC bid regimen.)

 Nevirapine Grade3/4 Liver Enzyme Elevations

Dr John Bartlett went on to further discuss concerns raised regarding antiretrovirals, particularly nevirapine and liver toxicity. Several antiretroviral agents may result in elevations in liver function tests or drug-induced hepatitis. Suggested risk factors for this type of toxicity may include concomitant chronic viral hepatitis, female gender, alcohol use, use of other liver toxic agents, allergic or hypersensitivity reactions and possibly concomitant nucleoside analogues (which may precipitate fat accummulation in the liver (steatosis) and lactic acidosis). Recently, the FDA in the US and EMEA in Europe have issued guidelines recommending frequent (2 weekly for 6-8 weeks) monitoring of liver function in patients initiating NVP. In the FTC-302 study described above, which was conducted in South Africa, 468 patients were enrolled, 385 of whom received NVP and 83 EFV. Fifty-nine percent of the patients were female and 87% black. All patients on treatment had completed a minimum of 24 weeks therapy.  Severe (grade 4) elevations in liver enzymes (defined as ALT, AST, alkaline phosphatase >10 times normal and total bilirubin >5 times normal) were observed in 36 (9.4%) patients in the NVP stratum and in none of the patients receiving EFV. Of these 36 cases, 33 occurred within the first four weeks of therapy; the onset date for the remaining three cases was week 32. Of the 36 cases, only one was HBsAg positive at screening with no evidence of active hepatitis, and 2 others had serological evidence of HCV infection. Incidence of grade 4 elevations was comparable between FTC and 3TC treatment arms (9% vs. 12%) but in females the incidence was twice that of males (12% vs. 6%, p = 0.05). In a multivariate analysis, female gender was the only identified risk factor. Two patients developed liver failure and died, one of whom was HBsAg positive at screening6. These data raise concerns about the choice of NVP in clinical practice and underline, consistent with recent recommendations, that liver enzymes in patients receiving NVP should be monitored closely, particularly during the first eight weeks.

T-1249: fusion inhibitor, cousin to T-20

Amongst agents targeting new viral targets, the fusion inhibitor T-20, developed by Trimeris and Roche, is the most advanced and genuinely exciting agent. Further activity data with this agent, which is currently dosed bid with subcutaneous injections (like diabetics administer insulin), will be the subject of a late breaker presentation on Thursday. Resistance to T-20 has been reported in in vitro studies, although currently commercial resistance tests are unable to evaluated T-20 resistance. The development of new fusion inhibitors with activity against viruses with apparent resistance to T-20 creates the potential for, as it were, ëresalvageí therapy after T-20 based ësalvageí therapy. This removes the perception that T-20 is the ëfinal chanceí or ëlast shotí with therapy, an important obstacle to early up-take of T-20 use. Importantly, this new fusion inhibitor, T-1249, again from Trimeris/Roche, is not only already in clinical development but may also have administration advantages over T-20.  Like T-20, T-1249 is a peptide fusion inhibitor and as such will not be suitable for oral administration. In laboratory and animal studies, T-1249 has demonstrated potent antiviral activity against a broad range of HIV-1, HIV-2, and SIV isolates and a resistance profile that does not overlap with T-20. The reported study evaluated the safety, pharmacokinetics and antiviral activity of T-1249 in a phase I/II dose escalation study. The study involved 72 HIV-positive, treatment experienced adults on no concomitant therapy and plasma HIV RNA >5,000 c/mL. Patients received T-1249 as monotherapy by sub-cutaneous injection for 14 days at doses ranging from 6.25 mg/day to 50 mg/day, on a once or twice daily regimen. The drug demonstrated dose-dependent activity (i.e. the more drug given the greater the fall in viral load). On day 14, the median change from baseline ranged from -0.10  at the lowest 6.25 mg/day dose up to -1.40log10copies/mL at the highest tested dose (50 mg/day). T-1249 appears to be eliminated from the plasma more slowly than T-20 providing the potential for once-daily dosing. Only two serious adverse events assessed as possibly related to study drug, occurred during the study; an allergic or ëhypersensitivityí reaction (involving oral ulcers, a rash and fever) in one patient and a marked fall in white cell count (neuropenia) in another. Otherwise, important clinical or laboratory abnormalities did not occur. Injection site reactions (soreness, localised swelling and redness) were mild and reported in the minority (40%) of patients7. As a maximal tolerated or effective dose was not established in this study, evaluation of higher doses appear warranted.


 The remaining presentations at this session provided insights in immune based approaches, adding agents into the regimen which do not have activity against HIV but instead potentially influence the way in which the immune system responds to HAART or may eradicate residual reservoirs of HIV infection. Both studies reported here evaluated agents used in other areas of medical practice, mainly in cancer chemotherapy. Cyclophosphamide is a chenmotherapeutic agent used to treat a range of malignancies. Ten treatment-naÔve patients with CD4 cells >200/mm3 initiated on HAART (stavudine, lamivudine and nelfinavir) and with  viral loads <50 (step 1) were randomized to add cyclophosphamide (n = 5) in escalating doses (750, 1200 and 1800 mg/m2IV) or continue ART alone (n = 5). Cyclophosphamide was well tolerated and only one subject required dose modification. Viral load levels remained <50 copies/ml through week 20 after randomization, although measurable RNA (ëblipsí) occurred more commonly in the cyclophosphamide group. In evaluating HIV DNA in peripheral blood and lymphoid tissue no differences were between groups but total lymphocyte counts and CD4+cells count (but not CD4%) were lower in the cyclophosphamide group. These limited data to not suggest that further studies with cyclophosphamide are indicated.


Interleukin-2 is already recommended for persons with no or modest CD4 responses to after 24 weeks of HAART in current French national HIV treatment guidelines. It is now being evaluated in 4000 patient global study assessing whether this agent delivers clinical benefits in persons on HAART with CD4 counts above 300 cells/mm3. The study reported here, evaluated IL-2 added to HAART relative to HAART alone in 204 patients initiating PI therapy with CD4 50-350. IL-2 (intravenous at 9 MIU daily for 5days every 8 weeks (n = 54) or subcutaneous at 7.5 MIU bid for 5days every 8 weeks (n = 55), was added after 12 weeks of indinavir + 2 NAs. Follow-up was for 84 weeks. Approximately 2/3 of patients completed 6 cycles of IL-2. IL-2 resulted in significantly greater increases in CD4 counts compared to HAART alone after 60 and  84 weeks of therapy. At the end of the study CD4 s were higher in the continuous intravenous dose increased CD4s more than the subc. dose arm (800 vs 600) which both had higher CD4s than no IL-2 arm (400). The presenter said the clinical data from this study suggested that IL-2 may show clinical benefit but this study was not powered statistically to answer that question.


1. Erickson-Viitanen S, Kaltenbach R, Getman D, et al. DPC 681 and DPC 684: Resistance and Cross- Resistance Profiles of Second Generation HIV Protease Inhibitors. 8th Conference on Retroviruses and Opportunistic Infections, Chicago February 4-8, 2001:Abstract 11.

2. Erickson J, Gulnik S, Suvorov L, et al.  A Femtomolar HIV-1 Protease Inhibitor with Subnanomolar Activity against Multidrug Resistant HIV-1 Strains. 8th Conference on Retroviruses and Opportunistic Infections

Chicago February 4-8, 2001:Abstract 12.

3. Gruzdev B, Horban A, Boron-Kaczmarska A, et al. TMC120, a New Non- Nucleoside Reverse Transcriptase Inhibitor, is a Potent Antiretroviral in Treatment Naive, HIV-1 Infected Subjects. 8th Conference on Retroviruses and Opportunistic Infections, Chicago February 4-8, 2001:Abstract 13.

4. Squires K, Gatell J, Piliero P, Sanne I, Wood R, Schnittman SM. AI424-007: 48-Week Safety and Efficacy Results from a Phase II Study of a Once-Daily HIV-1 Protease Inhibitor (PI), BMS-232632. 8th Conference on Retroviruses and Opportunistic Infections, Chicago February 4-8, 2001:Abstract 15.

5. Van Der Horst C, Sanne I, Wakeford C, Quinn J, Rousseau F. Two Randomized, Controlled, Equivalence Trials of Emtricitibine (FTC) to Lamivudine (3TC). 8th Conference on Retroviruses and Opportunistic Infections, Chicago February 4-8, 2001:Abstract 18

6. Bartlett J. Severe Liver Toxicity in Patients Receiving Two Nucleoside Analogues and a Non-Nucleoside Reverse Treanscriptase Inhibitor. 8th Conference on Retroviruses and Opportunistic Infections, Chicago February 4-8, 2001:Abstract 19

7. Eron J, Merigan T, Kilby M, et al. A 14-Day Assessment of the Safety, Pharmacokinetics, and Antiviral Activity of T-1249, a Peptide Inhibitor of Membrane Fusion. 8th Conference on Retroviruses and Opportunistic Infections

Chicago February 4-8, 2001:Abstract 14.

8. Bartlett JA, Silberman M, Miralles GD, et al. Antiretroviral Therapy (ART) Plus Cyclophosphamide (CTX) To Diminish HIV DNA in Lymphoid Tissue. 8th Conference on Retroviruses and Opportunistic Infections

Chicago February 4-8, 2001:Abstract 16.

9. Mitsuyasu R, Pollard R, Gelman R, Weng D.  Prospective, Randomized, Controlled Phase II Study of Highly Active Antiretroviral Therapy (HAART) with Continuous IV (CIV) or Subcutaneous (SC) Interleukin-2 (IL-2) in HIV-Infected Patients with CD4+Counts of 50ó350 cells/mm3: ACTG 328-Final Results at 84 Weeks. 8th Conference on Retroviruses and Opportunistic Infections, Chicago February 4-8, 2001:Abstract 17.

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