Amprenavir + Ritonavir (600/100 mg twice daily)

Brief Update from Montana: fires ain't the only thing in Big Sky state; remaining "burning" questions

600/100 APV/RTV bid APV+ABT-378/r For Highly PI Resistant HCV/HIV Coinfection

About 60 community were invited to Whitefish, Montana, in the shadows of Glacier Mountain Park, for a 3 day series of talks and updates on HIV & HCV/HIV coinfection treatment issues. The countryside was a mixture of big mountains and long stretches of flat range. I think the name Big Sky is used because the sky gives you a sense of great expansiveness both at night and during the day. Many of us took day trips to surrounding attractions and enjoyed ourselves immensely. Glacier Mountain Park was stunning. Some took helicopter rides over the glaciers. One brave soul took a two-seat airplane ride over Flathead Lake. The rocks in the Park are purple, I brought a few home with me. Flathead & Whitefish Lakes were also great and very enjoyable. I took a motor boat out onto Flathead Lake for several hours and it was very lots of fun. The now famous Montana fires continue  in the Southern & Northern parts of the state. We were in the North and at times you could smell the vague scent of burning fire. A light veil of smoke was at times observable. The food was generally horrible but the corn-fed steaks were delicious. I looked for Montana steers but couldn't see any on the local farms. So, I'm not sure where the steaks came from.

APV=amprenavir
RTV=ritonavir

The most relevant and interesting information reported at the GW meeting in Whitefish, Montana was on the potential utility of 600/100 APV/RTV bid for rescue therapy. GW presented their pharmacokinetics research on this subject and clinical plans. GW showed data sugesting that after adjusting for protein binding 600/100 APV/RTV bid (twice daily) may have a similar Cmin/IC50 ratio as ABT-378/r and therefore ought to be as effective clinically in individuals with PI resistance. In order to explore this possibility, they will be conducting a clinical study in HIV-infected comparing 600/100 APV/RTV to ABT-378/r. The new formulation of APV is currently being studied for equivalence to the current formulation of APV. The APV prodrug will be a single 600 mg cap or tab. A more detailed report ought to follow in near future.

Background on APV-
APV has always shown to have a different resistant profile, lending itself to the possibility of having certain benefits for initial & rescue therapy. APV's effectiveness in initial therapy this has been difficult to establish because of difficulties in adherence & tolerability. GI disturbances and high pill burden have been the hallmark of APV in human studies & clinical use. These difficulties have made it difficult to establish its effectivesness in clinical studies based on ITT analyses at 24 & 48 weeks, possibly due in part to discontinuation rates. Doubts about its antiviral effectiveness or potency have persisted although data suggests these doubts may be related to pill burden & side effects. GW is hoping that the new formulation's reduced pill count will lessen GI side effects and improve adherence. However, the only way to establish the true effectiveness and antiviral activity of APV is in human studies. These studies must be properly designed to address the key questions to which we need answers. In particular, APV's effectiveness in individuals with high viral load (>100,000 copies/ml) needs to be studied. Studies evaluating the new formulation of APV are ongoing and will be presented to the FDA for review. The study comparing ABT-378 to APV/RTV 600/100 bid should be interesting. An interesting and potentially effective treatment for individuals with extensive PI resistance may be to combine APV 600 mg with ABT-378/r. The coformulated capsule of ABT-378 already contains 100 mg of RTV. This ought to be studied. But, I don't think there is a study planned soon to look at this question.

For more backgound on APV see the following NATAP web site reports: 48 week APV Data:
 http://www.natap.org/march_2000/newsletter/48week_amprenavir_update_32300.html

APV Resistance Profile & Interactions with Protease Inhibitors & Efavirenz:
 http://www.natap.org/amprenavir10.html

GW is also researching 1200/200 as a once daily PI regimen. GW also discussed their ongoing research efforts & preliminary findings into the possibility that APV compares favorably to certain other PIs in leading to the several syndromes under the umbrella term called lipodystrophy: body changes, abnormal lipids, etc. Preliminary data suggest this may be true, but better defined clinical studies are required to confirm these suugestions.

Double PI Regimens & Resistance Testing- We discussed the concern that resistance testing is less helpful in trying to ascertain the potential effectiveness of a double-PI regimen for a person with extensive PI experience. For example, by combining 400 mg RTV with 400 mg IDV bid, a certain amount of PI resistance can be overcome, but how much? How do you decide how much resistance can be overcome? For the very PI resistant, 800 IDV + 200 RTV may be preferable because higher PI levels are achieved. But we don't have clear answers on that, only PK data. Phenotypic resistance testing is very limited in its ability to reflect on this question. Genotypic resistance testing may be more helpful but is still very limited as well.

HCV/HIV Coinfection: unanswered questions!! We also discussed the mounting and disturbing concerns about coinfection. There is a very small data set from a few studies of selected populations showing that individuals with coinfection responded as well to interferon+ribivarin as individuals infected only with HCV. Much more data from well defined studies are needed to truely assess this question. Further, the universe of coinfected individuals is comprised of a very diverse group. For example, some individuals have had HIV for 15 years and have had a CD4 nadir of <100 CD4s. Others have had HIV for less time and have much higher CD4s. These different patient groups may respond differently to HCV therapy. Individuals with low CD4 nadirs may not respond as well to HCV therapy despite increasing their CD4 counts to above 200 or even 500. Cirrhosis can develop despite HAART resulting in having <50 copies HIV RNA and >1000 CD4s.

Studies suggest that individuals infected with HCV alone with a strong CD8-cell or lymphocyte proliferate response to HCV antigen may respond better to HCV and HCV therapy. But, will individuals with coinfection have less of an ability to mount a CD8 response due to HIV, despite HAART? Is it advisable to start HCV therapy when CD4s are >500 or >800? The best opportunity for HCV "eradication" may be if a person starts HCV therapy when their CD4s are very high. It's possible that HCV treatment may be much less likely to achieve undetectable HCV RNA if started when the CD4 nadir is very low (<100).

How does triple coinfection including HBV affect response to HCV therapy? This needs study.

There is one small study (Benhamou Y et al. Liver fibrosis progression in HIV and hepatitis C virus coinfected patients. Hepatology 1999 Oct; 30: 1054-8) showing that individuals in that study who had above 200 CD4s could respond well to HCV therapy. This study suggests certain baseline thoughts from which to design further studies but cannot be used to form conclusions. This single study does not adequately answer the question of the response by individuals with low CD4 nadir (<100). Does HAART induce liver damage in HCV infected person? This is a remaining question that needs to be balanced by the data from the French study suggesting some coinfected individuals will respond well to HCV therapy.

A few studies suggest that in coinfected individuals HCV progression may be quicker and may in some instances progress very quickly. This suggests a person might want to consider HCV therapy prior to HIV therapy under certain circumstances. If a person has unstable HIV, low CD4s and/or high viral load, it may be more important to treat HIV first. If LFTs flare up after starting HAART, intervention may be required. The intervention could be simultaneous interferon treatment or stopping HAART and starting HCV therapy.

MAINTENANCE THERAPY
If a coinfected person cannot achieve undetectable HCV RNA, can they improve liver inflammation and slow fibrosis progression with continuing HCV treatment? Continuing therapy after inadequate or no viral load response is called maintenance therapy. Maintenance therapy is considered by many doctors for individuals who don't achieve sustained virologic response to interferon+ribivarin therapy. Studies suggest interferon has ant-fibrotoc affects despit virologoc non-response, which may sustain improved inflammation & fibrosis and buy time until new drugs are available. Two studies in individuals with HCV alone are starting up to answer this question. Will these studies answer questions for coinfected individuals? Should maintenance therapy consist of interferon or interferon+ribivarin? What dose of interferon should be used. These are unanswered questions.