Glasgow Wednesday Brief Update Report

This has turned out to be an interesting conference after all. Despite that the amount of new data is limited there have been several interesting talks and posters, and I've had some interesting conversations. David Back from the University of Liverpool, UK is a leading researcher in the area of HIV drug pharmacology (blood levels) and testing for drug blood levels, and how these areas relate to success of HIV therapy. He will be a guest on my radio show very soon ("Living well With HIV & Hepatitis", every Sunday on WOR 710 AM in NYC from 11pm-12 midnight; free tapes available online at www.natap.org). David Cooper is a leading Australian researcher in lipodystrophy and he will also be soon coming on the radio show to discuss his perspectives on lipodystrophy and bone problems.

ABT-378 & Resistance

This has been a controversial issue discussed at this meeting. Yesterday, I emailed a report on Abbott's data presented in Glasgow saying that treatment-naÔve study participants in ABT-378 studies, with >400 copies/ml, are not developing PI resistance (0/31 in study 863 with genotypes available do not have PI resistance). While in study there are 64 study 863 participants taking nelfinavir with genotypes available, with >400 copies/ml, and 20/64 have PI resistance. So, why aren't ABT-378 failures showing PI resistance and is this significant? I think its too soon to say how significant this is. But it does appear to be a phenomena. One explanation is that some of these individuals were non-compliant and so they may have had too little drug on board to develop resistance. Another potential explanation circulating is that ABT-378 drug levels are eliminated from the blood quickly if a person is non-compliant and so resistance may not develop. Abbott is suggesting and the it appears possible that resistance does not develop easily to ABT-378. Individuals who were found to be non-compliant were counselled. Abbott reported that 17/23 (74%) demonstrated resuppression at least once. While they said that only 11/51 (22%) taking NFV resuppressed. Again, I think its too soon to understand this, but in time we will see how real this is.

Bone Problems in HIV

Today. Antonia Moore from the UK reported results in an oral presentation from her study saying that bone mineral density (BMD) loss was associated with protease inhibitors and having AIDS. David Cooper went to the microphone and asked if she checked lactate levels. His Australian group is reporting their study results tomorrow. But at the Lipodystrophy Workshop in Toronto last month, they reported that BMD loss was associated with body weight before HAART and elevated lactate from nukes. They feel nukes leech the calcium or related materials from bone. They feel that mildly elevated lactate levels of 2 or 3 over a period of time will lead to BMD loss and osteopenia. And this could be worse of a problem for women. NATAP's web site has several reports on the Toronto Lipodystrophy Workshop and on BMD loss data reported there. There are several theories on BMD loss including that cytokine dysfunction may be related to bone loss. This would suggest that HIV or immune system restoration from HAART may be causative. As with lipodystrophy we do not know yet what's causing the BMD loss, but it does appear to be a problem for people with HIV who have had antiretroviral treatment. Several studies including the one today from Moore report higher incidence of BMD loss than in similar groups of people without HIV. I will report on Moore's talk hopefully tomorrow. At the DDW liver conference last Spring it was reported that as HCV progresses BMD a person may be more at risk for BMD los. So a person with HCV & HIV may have more risk for BMD loss. Diet, moderate weight bearing exercise and calcium supplements may be helpful.

Nevirapine & Hepatitis

There were two talks reported study data today from Spanish (Jose Gatell) & Argentinian researchers (Pedro Cahn) showing that nevirapine does not cause worse LFT or hepatitis problems than other PI therapy. Several comments from the audience and my feelings are that these studies were not well designed enough to be convincing. Even if true, we do not know the effect of HIV medications for people with HCV. A study needs to be done. Perhaps, people with coinfection should be treated for HCV first before HIV treatment. Certainly, a biopsy should be performed immediately upon discovering coinfection status.

Reported at Durban: Nevirapine Blood Levels Increase With Liver Dysfunction

(See Natap Durban Reports for futher details.) In 4 patients with moderate hepatic dysfunction (Child-Pugh class B), the nevirapine AUC was increased by 41%. Patients with moderate to severe hepatic dysfunction may require a reduction in nevirapine dose, either based on guidelines published in the package insert, or based on direct measurement of nevirapine concentrations, if available. from Charles Flexner, MD, Johns Hopkins.

Source: Medscape, Lamson M, Maldonado S, Hutman H, et al. The effects of underlying renal or hepatic dysfunction on the pharmacokinetics of nevirapine (Viramune). Program and abstracts of the XIII International AIDS Conference; July 9-14, 2000; Durban, South Africa. Abstract TuPeB3301.

Immune Function and When To Begin Therapy

There were two talks today about immune function, how much HAART restores the immune function, and how all this relates to "When to begin therapy?". A small dataset reported by Michael Lederman from Case Western and the ACTG suggests that HAART restores key immune function but it's partial restoration. I think it has been generally accepted that immune restoration from HAART is partial. Complete "repertoire" deletions may not be replaceable. That is, certain losses in the immune system may be complete and not recoverable.

A key question which I don't think we know the answer to is: how clinically relevant are these losses. Certainly, it appears that key opportunistic infections do not emerge after CD4s have been increased after HAART if CD4s had declined to low levels. That is for most people. But, what about those individuals who are unable to generate a CD4 increase after HAART which reduced their viral load to <50 copies/ml. And, is a CD4 increase after protective for 10-20 years against cancers and other immune related problems that can occur?

I think the answer is we do not know. So, waiting to begin therapy for "too long" may expose a person to risks. We don't know when a person needs to begin therapy to absolutely prevent them from losing too much immune function to leave themselves unprotected against key HIV infections as well as other potential problems such as malignancies & cancers. Lederman said CD4s coming back up are not the same as before decline. There may be qualitative & quantitative differences.

So, although it appears that if you wait to begin HIV therapy til CD4s are 200 or 350 you may be able to prevent infections such as CMV, PVP, etc, immune restoration is partial and it is not known if you may be permanently losing immune function that you may need in the future. Although you may be able to delay onset of lipodystrophy and other unwanted toxicities or side effects, but at what cost. A speaker from the NIH said today that we need a large study on when to begin therapy to answer this question. I think it would take a 10+ year study with 10,000 patients to possibly be able to answer the question. I have not changed my mind. I think such a study is not feasible and conditions will change such that any answers will not be applicable. Would you enroll in such a study and leave such an important treatment decision to the flip of a coin?

Additionally, I think a person's immune system is personal and immune response is individual. So I think a large study would yield general results but when to begin therapy should be more individually based. One person may progress more quickly than another. One person may want to begin therapy early because they don't want to take the chance that they will lose immune function. Finally, CD4 recovery may not be as good so waiting til one's CD4s are 200 and then being unable to increase CD4s to much higher will leave person in untenable situation.

IL-2

There is an interesting poster from the research group at Chelsea & Westminster in London. I'll report more details later but essentially they conducted small study with treatment-naÔve individuals who had undetectable HIV viral load on HAART. After 17 weeks on HAART patients with CD4s >300 and <500 copies/ml received IL-2 subcutaneously (5 MU) bid for 5 days at 4 week intervals. T cell & viral load tests were done on days 1 and 5 of the IL-2 treatment cycles. CD4s were 965 and viral load <50 copies/ml after 3 weeks after follow-up following cycle 3. 7 of the 10 patients experienced a small viral blip on day 5 of at least one of the IL-2 cycles (range 51-355). Can this be a risk for resistance to develop? I think there is a risk, but a number of studies have not seen resistance developing. Interestingly, the study authors suggest that lymphocyte proliferative responses they observed for these individuals which coincided with the blips may be like IL-2 induced , HAART controlled autovaccination and would be a viable alternative to structured treatment interruptions. In other words, these viral blips might stimulate an immune response leading to better control of HIV.

I must run off now to poster reception at Scottish Exhibition Convention Center. More reports will follow.