Dear Doctor,

i'am nicholas from italy. i'm 39 and since september 95 i discovered i was hiv pos. since feb 96 i've been under therapy ,in the beginning with norvir,azt and ddi. after 2 years doctors decided to change my therapy but things are not going well. cd4 are only 55 and viral load is 775000. i'd like to know if there is any chance to have gene therapy in italy or something better as traditional treatment. right now i'm taking norvir 125 mg once a day, abacavir 1 tabs twice a day,invirase 3 tabs twice a day. thank you

First - I don't know about the research into gene therapy in Italy. Your own doctor should be able to call some of the research centers that focus on HIV in the major academic centers in Italy - there are centers in Rome and Milan, and I am sure other places as well. However, none of the work so far done and presented has shown evidence of being helpful for someone who describes what you have... so let's review other options.

I don't know if you have mentioned every antiviral you have ever taken, but assuming you have... then it sounds like you have an HIV strain that has developed significant resistance to the effects of norvir/ritonavir, invirase/saquinavir, and abacavir. Why did this happen? Two reasons may be involved for you. First, your initial combo was azt/ddI/norvir - and your HIV developed resistance to it - then your second combination that you are now on will have a harder time working for you as well. This is because of a problem known as cross resistance - meaning that the "tricks" or genetic mutations HIV learns when it became resistant to your first combo also helped it learn to resist the effects of your next combo.

The other problem may be one of blood levels of your meds - I have not heard of that dosage of norvir given just once a day to be enough to boost the level of invirase into a range where it is active. It may be true - as there is always new research going on - but it sounds a bit lower than most of the work that has been done so far. Most of the time norvir is given twice a day - so you may want to be sure of that dose you are taking. Doses of 100-200 mg taken twice a day however are being used to boost the blood level of a second protease inhibitor, such as invirase.

Even if the dose of norvir is thought to be enough to boost the invirase to a therapeutic level - then you are on only two antivirals - since that dose of norvir is only acting to boost the invirase, and not to be useful as an antiviral. But as I mentioned earlier - resistance from the norvir can decrease the chances of invirase being successful. And your viral load suggests that HIV figured these three meds out.

What to do? Well - there are other protease inhibitors that may be available to you that you have not taken yet - including a new one called amprenavir, as well as nelfinavir, and indinavir. However - resistance from norvir often results in less success from indinavir, tho some might try a norvir/indinavir combo. The other two protease inhibitors may have something to offer - as resistance from other PIs is sometimes successfully treated with these other meds. They could be taken together although both have diarrhea as a side effect, so that may not be too successful... so you may only be able to tolerate one of them. And they will need other antiviral "company". What can you take with them?

Well, you have not mentioned d4T, but that will only offer a little additional potency for you. One approach that is a consideration when you start d4T is also adding hydroxyurea when restarting the ddI (and maybe staying on the abacavir). This would be controversial given your CD4 count since hydroxyurea does limit the CD4 increase - but it may result in more successful HIV control and for that reason some of us are trying it even in this circumstance.

Your biggest consideration is whether or not to "use" a nonnucleoside (such as delavirdine, nevirapine, or efavirenz) in your next combo. These meds are powerful - but again need company to work well. And it is not clear if you have enough potent company to take advantage of this as yet unused class of medications. Some would therefore hold on and not use any of them yet - since there are new meds in development that in the next year or so might be more powerful company than anything we now have to offer - and using the nonnuke then might result in a much more successful result than using it with the meds you now have available. And you likely get one good chance that you can count on in this class of meds as far as we can tell...

Your next combo could be just a few meds like I have mentioned above - such as nelfinavir with d4T and ddI with hydroxyurea. However, another approach has been to just take as many antivirals as you can in this next combo - like amprenavir/nelfinavir/d4T/ddI/abacavir/hydroxyurea - and see if that works (and is tolerable to you...). We don't know yet which way would be more successful.

Finally - even if you cannot get your HIV viral load all the way down to below detectable with this next combo - we have learned that just partial control might produce a boost to your T4 count that might just last you long enough until the next wave of meds becomes available. So your challenge is to see which of the current meds can act as a bridge until then.

Hope that helps.

Cal Cohen, M.D., M.S.