CROI news: bite size new drugs…
2 March 2011. Related: News.
Bite size news from CROI today includes links to interesting studies on new drugs in development.
- an integrase inhibitor that works against raltegravir resistance
- a new oral entry inhibitor
- a formulation of tenofovir in early development
- first results of a new hepatitis C drug in HIV-positive people with HCV coinfection.
New integrase inhibitor: dolutegravir results in people with raltegravir resistance
This morning included a session on new drugs with several important studies. This included early results from using the integrase inhibitor in development from ViiV (GSK/Shionogi, formerly called GSK 572) now named dolutegravir. 
Although raltegravir generally worked very in people with multiple drug resistance, helped by the ability to use new drugs like darunavir/r and etravirine in the background combinations, some people still developed integrase inhibitor resistance. These are generally people with few other treatment options who are now waiting for new drugs.
Although a 50 mg once-daily dose was initially studied, this was quickly changed to 50 mg twice-daily when the lower dose failed to show sufficient responses. This 50 mg twice-daily results included 24 people who added dolutegravir to their failing combination for 11 days (and dropped raltegravir if they were still taking it). To be included in the study people needed to have at least one additional drug that would be active, and this was added to dolutegravir on day 11 when the background combination was optimised, based on resistance test results.
Nearly all patients (23 out of 24) either reduced their viral load to less than 400 copies/mL or by at least 0.7 logs). The average (mean) drop in viral load at day 11 was –1.76 logs for study as a whole and –1.57 for people with integrase mutations (Q148 + others). This compared to –1.45 logs seen in the initial 50 mg once-daily study.
The 50mg twice-daily dose has now been selected for phase 3 studies in people who have integrase inhibitor resistance to raltegravir or elvitegravir.
A new oral entry inhibitor from BMS
On Monday, we heard about an entry inhibitor in development from Bristol-Myers Squibb called BMS-663068. This is interesting because, like other entry inhibitors, it works before the virus gets into a CD4 cell. So this has the potential to be a new drug in a new drug class. 
The study reported results from using this drug for eight days only, without other drugs, in 50 people who had not previously used HIV treatment.
The study looked at five different doses, including once-daily and twice-daily, with and without ritonavir boosting. After eight days most doses had reduced viral load by 1.6 logs (by about 95%), which is a good level of activity.
These short studies only really determine the general level of activity and that there are not side effects that are serious enough to restrict further research. Side effects when reported were mild and no-one discontinued the study. Drug levels suggested that ritonavir boosting may not be needed and phase IIb trials in people with drug resistance are planned to start later this year.
A new version of tenofovir in early studies
A study of new formulation of tenofovir (called GS-7340) in development by Gilead reported first antiviral activity. 
This compound is designed to achieve higher levels of the active compound in specific tissues such as lymph nodes and target cells compared to tenofovir, without increasing kidney toxicity.
The study randomised 30 HIV-positive people who had never used HIV treatment to either 50 mg or 150 mg of GS-7340 or to standard dose of 300 mg tenfovir (with ten people in each group). After 14 days these three groups produced viral load reductions of –0.95, –1.07 and –0.54 log respectively. Blood levels were lower than the tenofovir group, but cells levels were higher.
Although these are early results, the hope is that formulations that require lower doses can be coformulated more easily with other antiretroviral drugs, and that lower doses might potential reduce the most reduced cost of drugs used in developing countries.
New oral hepatitis C drug: first results using telaprevir in HIV-positive people
Mark Sulkowski from Johns Hopkins University presented the first results from using a new drug for hepatitis C (HCV) in people with HIV and HCV coinfection. 
Telaprevir is a drug that needs to be taken three times a day and it still needs to be used in combination with the current treatment of pegylated interferon and ribavirin. Studies in HIV-negative people have shown significant benefits compared to current treatment with peginterferon plus ribavirin and has the potential to shorten the treatment period.
All participants in this study were HCV genotype 1, HCV treatment naive and pegylated interferon plus ribavirin was used by all patients for 48 weeks. However, for the first 12 weeks people were randomised to either telaprevir or placebo.
Part A of the study (in up to 20 people) was in people not on HIV drugs and part B included people on HAART. The concern for drug interactions meant that the HIV drugs used were either efavirenz or atazanavir/r plus tenofovir and either FTC or 3TC.
The study details were quite complex in order to reduce the risk of developing resistance to the HCV drug. However, telaprevir with or without HAART led to impressive early reductions in HCV viral load compared to the placebo group at week 4 (70% vs 5 %) and week 12 (68% vs 14%). These are early results. With hepatitis C drugs, the important results are remaining free of hepatitis C six months after stopping treatment. Although this is often related to good early responses at 4 and 12 weeks, we really need the full study results.
Telaprevir has side effects – it is taken with interferon and ribavirin, so nausea, fatigue, rash, itching, dizzyness, diarrhoea, vomiting etc were still common – but only two people discontinued all treatment due to side effects: one with jaundice and one with anaemia.
Nevertheless, these early responses are impressive and they are in the most difficult to treat genotype-1 form of hepatitis C.
- Eron J et al. DTG in Subjects with HIV Exhibiting RAL Resistance: Functional Monotherapy Results of VIKING Study Cohort II. 18th CROI, 27 February–3 March 2011, Boston. Abstract 151LB. http://www.retroconference.org/2011/Abstracts/42541.htm
- Nettles R et al. Pharmacodynamics, Safety, and Pharmacokinetics of BMS-663068: A Potentially First-in-class Oral HIV Attachment Inhibitor. 18th CROI, 27 February–3 March 2011, Boston. Oral abstract 49. http://www.retroconference.org/2011/Abstracts/41942.htm
- Markowitz1 M et al. GS-7340 Demonstrates Greater Declines in HIV-1 RNA than TDF during 14 Days of Monotherapy in HIV-1-infected Subjects. 18th CROI, 27 February–3 March 2011, Boston. Oral abstract 152LB. http://www.retroconference.org/2011/Abstracts/42549.htm
- Sulkowski M et al. Interim Analysis of a Phase 2a Double-blind Study of TVR in Combination with pegIFN-a2a and RBV in HIV/HCV Co-infected Patients. 18th CROI, 27 February–3 March 2011, Boston. Oral abstract 146LB. http://www.retroconference.org/2011/Abstracts/42467.htm