Eagerly awaited results from three pivotal safety and efficacy studies of HCV treatment in HIV/HCV coinfected individuals were presented at the 11th Conference on Retroviruses and Opportunistic Infections. Tracy Swan prepared this short summary for TAGline.

Three large clinical trials, ACTG's A5071, Roche's APRICOT and ANRS HC02 (RIBAVIC), reported that combination therapy with pegylated interferon plus ribavirin was more effective than standard interferon plus ribavirin. Despite the superior efficacy of pegylated interferon, HCV treatment is less effective in coinfected people than in those with HCV alone. In HCV monoinfection treatment trials, sustained virologic response rates (SVR; no detectable HCV in the bloodstream six months after completion of HCV therapy) have ranged from approximately 40% in genotype 1 to >70% in genotypes 2 and 3. Direct comparison across studies is complicated by differences in sample size, baseline characteristics of their participants, brand of interferon used, dose of ribavirin and use of hematological growth factors.

Several factors contributed to differences in response rates in these studies. Although APRICOT was far larger than the other two trials, its results are not generalizable for several reasons. APRICOT used a higher dose of ribavirin (800 mg/day) than A5071's initial dose (600 mg/day, escalated gradually), and a different type of pegylated interferon (alfa-2a; Roche's Pegasys) than ANRS HC02 (alfa-2b; Schering's Peg-Intron). Study populations differed; a majority of APRICOT's participants had favorable prognostic factors: well-controlled HIV disease, high CD4 cell counts, low body weight and mild-to-moderate liver damage. A much larger proportion of ANRS HC02 participants had bridging fibrosis or cirrhosis. Blacks-in whom HCV treatment is less effective-constituted only 10% of APRICOT while approximately 30% of A5071's participants were African-American.

The usual interferon-associated side effects-flu-like symptoms, fatigue and depression-were reported in all three trials. Laboratory abnormalities included thrombocytopenia, neutropenia, and anemia. Both ACTG A5071 and APRICOT allowed investigators to use growth factors for management of treatment-induced anemia and neutropenia; none were used in ANRS HC02, which may have contributed to its high discontinuation rate. During APRICOT, two deaths considered possibly or probably related to study drugs occurred; one from cardiac arrest and one suicide during hospitalization for depression. High dropout rates, serious adverse events and deaths underscore the need for less toxic treatments, multidisciplinary care and support during HCV treatment.

Until more effective and less toxic treatments for hepatitis C are available, strategies for optimizing the efficacy and tolerability of pegylated interferon and ribavirin are needed. The 24-week course of treatment for HCV monoinfected individuals (standard of care for monoinfected individuals with genotypes 2 and 3) may not be adequate for coinfected people; high relapse rates after the end of treatment have been reported in previous studies. In APRICOT and A5071, relapse rates in genotypes 2 and 3 were low (from 64% to 62% at week 72; from 80% to 73%, respectively). Extending treatment from 48 weeks to 72 weeks in genotype 1 merits further investigation.

In the meantime, it may be necessary to revisit the treatment paradigm for hepatitis C. Slowing HCV disease progression and improving liver health may be a more realistic outcome for many coinfected people than eliminating hepatitis C. Improvement in the condition of liver tissue may occur in the absence of a sustained virologic response. In A5071, histologic improvement occurred among 9/26 (35%) of virologic non-responders. Maintenance therapy with low-dose pegylated interferon may be an option for virologic non-responders with advanced liver disease.

Some of the lessons learned from these trials are:

• Treatment with the full dose (800 mg/day) of ribavirin appears to be more successful than dose-escalation.

• The likelihood of achieving a sustained virologic response is extremely low unless HCV RNA is either undetectable or decreases by 2 logs at week 12.

• Growth factors ought to be used for management of anemia and neutropenia during HCV treatment rather than dose reductions.

Although Roche's Pegasys appears to be the therapy of choice for coinfected people, in the absence of a head-to-head study comparing efficacy and tolerability of both products, we cannot be sure. Selecting the type of pegylated interferon may not be the most crucial element in an HCV treatment decision. These studies have led to other pressing questions. Schering and Roche could compare the efficacy and tolerability of their products, or use their resources to sponsor trials that answer questions such as:

• What are the most effective side effect management strategies?

• Should interferon-induced depression be treated pre-emptively, or on an as-needed basis?

• In HCV monoinfection, those with high HCV RNA (Ž800,000 IU/mL) are less likely to achieve sustained virologic response. Since HCV RNA levels are significantly higher in coinfected people, 800,000 IU/mL may not be an accurate threshold in coinfection. Is there a prognostic threshold in coinfection, given the higher viral loads? If so, what is it?

• Extending treatment for an additional 24 weeks may lower the relapse rate in genotype 1. How can clinicians identify individuals who are most likely to benefit from additional treatment?

• There have been a few reports of sustained virologic response among people who did not have undetectable HCV RNA or a 2 log decrease at week 12. Is there any way to identify people who may to achieve sustained virologic response although they did not have an early virologic response?

• How can we identify those who will have histologic improvement in the absence of a virologic response?

An attribution omission in Tracy's HCV pipeline article of February neglected to recognize the contributions of Daniel Raymond. TAGline regrets the oversight. ¤

Pipelines are almost as delicate and fragile as the ecosystems they go trampling through, writes TAG's Antiviral Project Director Rob Camp. Oft-times the way to get from the beginning to the end is not a straight line. Although that does remain the quickest way geometrically, there may be other factors at play. For oil to get to the Black Sea, sometimes the pipeline has to go around countries and political factions, rather than through them. And on the way, discoveries are made and decisions are taken.

Last year's pipeline report was warm and hopeful and excited. But over the course of the past year, we witnessed the demise of SCH-C, Roche dropped development of a second generation fusion inhibitor, and both integrase inhibitors (Shinoigi and Merck) have also been given the 'ole heave-ho.

In other disheartening news, Gilead sold back its Phase II nuke, DAPD, to Emory University. With many difficult side effects ("lenticular opacities," kidney concerns) and not enough ingenuity regarding how to make a "salvage" drug work better, they gave up. Maybe a "real" salvage company, as Boehringer-Ingelheim now describes itself, would be interested in picking up a Phase II nuke?

So I am putting the TMC compounds (the protease inhibitor, 114, and the non-nuke RTI, 125) and tipranavir back in the pipeline-because otherwise not much will be coming out of it in the near to midterm future.

Nukes

D-D4FC/Reverset
Reverset is an NRTI with activity against HIV, an intracellular half-life of 17 hours, and no reported mitochondrial toxicity, with in vitro activity against AZT and 3TC resistant mutations (but not the D69 or Q151 mutants). Pharmasset offered up a 10-day monotherapy dose escalation trial in treatment naïve people >50 CD4s, at 50, 100, 200 mg QD.

Although 200 mg showed the best pharmacokinetic (PK) data, CD4s increased the best with 100 mg, and viral load at 100 mg dropped by 1.80 log10 (200 mg not reported). Enteropathy (an intestinal disease) and bone marrow toxicity has been seen in rats. Hypopigmentation has been seen around the nose in female dogs. In humans, without grading, headache was seen in 33% of patients, fatigue in 17%, and the cold symptoms in 46%.

ACH-126,443/elvucitabine
ACH-126,443 is a new nucleoside analogue said to have activity against 3TC resistant HIV-and HBV-and is under development by Achillion Pharmaceuticals. Its chemical name is beta-L-Fd4C, and its generic name is elvucitabine. ACH-126,443 is a strong candidate for once daily dosing, with an intracellular half life of more than 20 hours.

In vitro studies have also looked at the impact of this compound on mitochondrial DNA. ACH-126,443 caused no mitochondrial toxicity, and reduced the level of mitochondrial damage caused by d4T when the two drugs were combined in the test tube.

A Phase II study was conducted to assess the anti-HIV activity and safety of ELV in a HAART regimen in persons with the principal 3TC mutation (M184V). Fifty-six individuals remained on their 3TC-containing HAART regimen and then switched their 3TC for ELV (at either 50 or 100 mg, QD). While the drug demonstrated good antiviral activity, unexpectedly high toxicity (4 of 56 patients needed to discontinue treatment) caused the study to be prematurely terminated (one year ago March). Lower doses are expected to be studied.

DAPD/amdoxovir
Also known as DAPD, amdoxovir is an investigational guanosine nucleoside analogue currently in Phase II development for the treatment of HIV. Amdoxovir has also been tested in humans for the treatment of chronic hepatitis B infection and is currently in Phase II clinical trials. In one of the more recent studies of the drug (reported at the Boston '03 Retrovirus conference), five of eighteen study patients discontinued the study due to "lens opacities."

Gilead acquired the worldwide rights to amdoxovir, through a licensing agreement with Emory University and the University of Georgia Research Foundation, when it acquired Triangle Pharmaceuticals in January 2003. But this past January 28, Gilead announced that it was giving the drug back to the two academic centers, Emory University and the University of Georgia, and ending the agreements "for strategic reasons."

Gilead explained it would meet its ongoing obligations with respect to existing clinical trials and is committed to cooperating with the universities during the transition of this technology to a new licensee.

Mary L. Severson, Ph.D., Chief Technology Officer at Emory University, recently stated that ""Amdoxovir has great potential for salvage therapy in HIV infected individuals" and that "Emory and the University of Georgia Research Foundation are committed to the continued development of this drug and the ongoing NIH-sponsored clinical trials ACTG 5118 and ACTG 5165."

MIV-310/alovudine
MIV-310, alovudine, active against multi-resistant HIV is a patented pharmaceutical compound in the NRTI class. Phase IIb trials are directed towards identifying the optimal dosage to maximize virus reduction with acceptable side-effects.

Non-nukes

Capravirine
Phase 1 trials suggest that capravirine is ten times more potent than current NNRTIs. A dosing study reported that 2,100 mg capravirine twice daily produced a 1.69 log reduction in viral load after 10 days of treatment. This was equivalent to the viral load reduction in the triple therapy control arm.

Capravirine is active against HIV variants with single mutations at codons K103N or V106A or L100I which confer resistance to NNRTIs. Capravirine is likely to be active against viruses with resistance to efavirenz. Resistance to nevirapine (usually characterized by a mutation at codon Y181C) would render capravirine useless. However, a mutation at codon 181 or a dual mutation at codons 103 and 100 will confer high level resistance to this compound, calling into question its usefulness.

Clinical trials of capravirine were suspended pending safety checks following the discovery that the drug causes vasculitis (inflammation of the blood vessels) in dogs. Vasculitis may cause severe damage to the tissue supplied by inflamed blood vessels because blood cannot adequately reach the tissue. Development has now resumed. In a phase II study, a higher rate of nausea, vomiting and diarrhea was seen in the 2,100 mg group, and so the 1,400 mg dose has now been selected for further development. Capravirine is currently being tested in two international studies. One is testing the drug in treatment-naive patients, and the other is testing the drug in combination with nelfinavir and two new NRTIs in patients who have failed or did not respond to an NNRTI-containing regimen.

Capravirine is also being tested in studies where it is combined with drugs that are p450 cytochrome inhibitors, because these have been shown to boost plasma levels of the drug. Taking the drug with food also increases blood levels. A study in healthy volunteers showed that capravirine reduced lopinavir levels somewhat, but that lopinavir increased capravirine levels substantially.

Calanolide-A
One year ago to the month, Sarawak MediChem issued a press release explaining that they had completed a 48-subject (HIV-negative) PK and dosing trial of Calanolide A in combination therapy for HIV. That was March 4, 2003. There's been little word since. The best clues may be had at the web site of the Sarawak half (not the Advanced Life Sciences half) of the partnership:

"In our Phase IB studies we tested calanolide A with different twice-a-day regimens for 14-days in 32 HIV-infected patients. The studies showed a trend in viral load reduction as the dosing was increased. Furthermore, there was no evidence of the emergence of viral mutants over the period of study possibly indicating that calanolide A can delay the onset of drug-resistant viral strains. We plan to conduct Phase I/II clinical studies throughout 2002-03 and progress quickly to Phase II/III in 2004."

TMC-125
A lovely resistance poster laid out the susceptibility codons of TMC-125. They seem to be at positions 101, 179, 181 and possibly 227 and 230, decreasing the efficacy of the drug. These four single mutations and one double mutation are worrisome (they cause a >10 fold change, although 4 may be the more realistic fold change to be concerned about. Looking at 4 fold, the 100, the 108 and 238 may be important, along with doubles at 181 + 188, 181 + 190, 179 + 181). A number of (at least six) triple mutations are worrying. No efficacy data were presented; they have just started a number of trials after a nine-month hold due to rash issues that have now been "accepted" by the FDA.

The DPCs: Dupont follow-ups
When BMS bought Dupont, they inherited a lot of non-nuke RTIs (chief among them DPC-086 and DPC-961). We thought they had forgotten about them. While clinical development of DPC-086 (aka BMS-561390) and 961 was officially terminated 2 years ago, tricyclic non-nukes shall be back!

Protease Inhibitors

Tipranavir/r
Originally developed by Pharmacia & Upjohn, tipranavir was acquired by Boehringer-Ingelheim, the maker of nevirapine. Following encouraging results in phase I/II clinical studies, tipranavir is now in phase III studies.

The formulation of tipranavir (TPV) used in early trials produced low concentrations of the drug. It was subsequently replaced by a SEDDS formulation. However, average plasma concentrations tipranavir remained mediocre, so investigator have turned to concurrent dosing with low-dose ritonavir, which boosts blood concentrations of tipranavir. The dose of tipranavir that will be studied in the Phase III clinical program is 500 mg of tipranavir taken with 200 mg of ritonavir twice daily. This dosage was found to be safe and effective. Blood levels of TPV are increased with a high-fat meal.

Tipranavir is able to reduce viral load by up to 1.5 log when dosed with 200 mg of ritonavir. This small dose of ritonavir can substantially improve the drug's pharmacokinetic profile (and reduce the daily pill burden). When taken without ritonavir, tipranavir has reduced viral load by between 0.8-1.3 log after two weeks. The addition of ritonavir may also delay tipranavir clearance for long enough to allow once-daily dosing.

A study known as RESIST (Randomized Evaluation of Strategic Intervention in multi-drug ReSistant patients with Tipranavir) is evaluating tipranavir in people who have taken nucleoside analogues, NNRTIs and protease inhibitors. It is studying the safety and efficacy of tipranavir boosted with low-dose ritonavir versus a low-dose ritonavir-boosted protease inhibitor that is chosen on the basis of treatment history and baseline resistance testing.

The RESIST study is being conducted in more than 280 clinical trial sites worldwide. Studies of drug interactions with other protease inhibitors are also taking place. These studies are likely to report their findings during 2004 and it is expected that the drug will be licensed in the United States by the end of 2004, with Europe following in early 2005.

Tipranavir was developed as an alternative to existing protease inhibitors which display a high level of cross-resistance. Test tube studies report that resistance to tipranavir is slow to develop, and that there is no clear pattern of cross-resistance to currently available protease inhibitors.

More recent findings, however, suggest that patients with three or more PI-associated mutations are unlikely to experience an optimal response to TPV/r. When analyzed by the number of baseline PI-associated resistance mutations, successful virologic response was clearly associated with two or fewer mutations. These findings raise the question of whether tipranavir will be able to salvage treatment failure associated with loss of previous PI susceptibility, and have been an important focus of phase III studies.

Resistance mutations associated with tipranavir are I15, E35D, N37D, D60E and A71T. Isolates with resistance mutations at codons 82T and 84 have also displayed reduced sensitivity to tipranavir. Other secondary mutations appear to be important in such cases for determining how much sensitivity is lost.

TMC-114/r
Unfortunately, TMC-114 needs 100 mg of ritonavir, usually BID, but otherwise may be considered an advance in protease inhibitor therapy. Food also helps exposure (by some 40%). Response rates in this dose escalation study were similar, if not identical (by statistical analysis, not per person studied), for patients with >1 primary protease inhibitor mutation, phenotypic resistance to all protease inhibitors, phenotypic resistance to lopinavir, and viral loads of more than 20,000. Baseline susceptibility to TMC was not predictive of these positive effects. ¤

Source: Data Monitor (and individual company reporting)

* As APRICOT (the AIDS Pegasys Ribavirin Internatioal Co-Infection Trial) was an international study, not all Black participants were African-Americans.
†SVR= Sustained Virologic Response (HCV RNA <50 IU/mL for >24 weeks after discontinuation of treatment)