THERAPY INTERRUPTIONS
     from Jules Levin, NATAP

Question from reader: What is the update with HAART interruption studies - I have heard that as many as 50% of HIV positives who stop HAART after a year of being undetectable show that their own immune systems are stably inhibiting HIV replication for the long term.

There are several situations in which therapy interruptions (STI: structured therapy interruption) have been researched and considered in practice. In addition, several various approaches are being explored in research including combining HAART with immune based therapies. Oftentimes, the potential risks or harm of taking a treatment interruption do not receive the same attention as the appealing aspects. Below is a summary report on this subject including the risks and unknowns.

Therapy Interruptions in Acute Infection

Interrupting therapy in people treated with HAART during acute infection (very soon after infection) appears that it may be useful and that is the situation in which you heard about individuals staying undetectable. If you want to read an article by Eric Rosenberg, the researcher of that study, the article is described below (at he end of this report) and can be read on the front page of the NATAP web site <www.natap.org> This article explains his research findings. Rosenberg & colleagues at Mass General treated a small number of HIV-infected persons with HAART during acute infection. After repeated therapy interruptions I think it's 5/8 have maintained control of HIV viral load at a low level without HAART. Now, this approach also has been subject to some scrutiny. For one, finding people to treat in acute infection stage is very difficult and does not have broad usefulness to most people with HIV. Second, this study has not clearly established a cause-effect relationship. The study has not clearly shown that interrupting therapy controls HIV without drugs, although it appears to.

Interrupting therapy in persons with Chronic HIV and Undetectable Viral Load

Several studies have been conducted looking at the results after several sequential interruptions. The initial goal or concept was that several interruptions might stimulate an immune response that could control HIV replication without HIV therapy. There is little or no evidence so far from these studies that interruptions will accomplish this goal. Preliminary results from the largest study conducted to date were reported by Bernard Hirschel from Switzerland at Durban and updated at Glasgow and were very discouraging. You can read a report on this study in the Glasgow Conference Report on the NATAP web site.

One small Spanish study in ten individuals showed some individuals treated in early but not acute infection may benefit from interruptions in terms of controlling HIV without therapy. The Hirschel study did not show any consistent ability to control HIV by interrupting therapy. Most people who interrupted therapy were not able to control HIV although it appeared as though a few might. You can read about the small Spanish study and other related STI reports from the Resistance Workshop in the Conference Report section on the NATAP web site (link below). You can read the NATAP report about the Hirschel study in the Glasgow Update section on NATAP web site (www.natap.org) but here is title of article & link:

Swiss-Spanish Strategic Interruption Study in Chronic Infection in Group Well Controlled Virologically

"...only 17% were able to control HIV <5000 copies/ml after several interruptions; 80 patients have had 4 interruptions and median viral load during interruptions has not declined. But additional studies will be looking at interruptions".

Small Spanish Study: Continuous and spontaneous control of plasma viral load after 8 months without therapy and 3 cycles of therapy interruption in chronic HIV-1; correlation with induced cytotoxic (CTL) and helper HIV-1 specific immune responses.

Here's a related link: Structured Therapy Interruptions

Taking a Drug Holiday

A person may want to stop therapy just to take a break from the drudgery of regimentally taking their HIV therapy, and the question is can it be harmful (see risks discussed below). Mike Saag reported a study on this question at ICAAC. His findings suggest to me that it was a problem in general for the people he studied, although it appeared he concluded otherwise. The study was called "Treatment Interruption & Affect on CD4 & Viral Load" and can be read in the ICAAC Conference report section on NATAP web site. Here is direct link to article:

"Treatment Interruption & Affect on CD4 & Viral Load"

Stopping Therapy When Viral Load is Detectable For Person With Extensive Drug Resistance

German researchers (Veronia Miller) suggested two years ago that persons in her clinic who stopped therapy who had detectable HIV and were very treatment experienced could stop therapy & reverse resistance. In other words, they would now be sensitive to the drugs they had resistance to just due to stopping the drugs for a period of time. This flew in the face of resistance experts who said it made no sense. In fact, one year later Miller reported these individuals had severe CD4 decreases, viral load increases, opportunistic infections emerged, and it was shown by several research efforts that resistance did not revert to sensitivity.

More Research Is Indicated

Although research so far has not shown promising results in terms of being able to control HIV replication following repeated interruptions, I think there are still doubts about these findings. And, of course we remain unsure about potential risks such as resistance developing. More research is needed to take a complete look at various approaches to STIs to get a more complete sense of whether or not it's useful. As well, research can better characterize potential risks. Patients are taking drug holidays or self-imposed interruptions, whether they tell their doctors or not. Even if research proves interruptions are not useful and too risky, at least this would inform patients more completely.

WHAT ABOUT RISKS OF TAKING THERAPY INTERRUPTIONS

What About Repeated Interruptions Causing Resistance?

This is a main concern about the potential risk of interrupting therapy. Several studies have shown that in general resistance has not developed with several repeated interruptions, although a few cases of resistance have been identified. Some researchers remain concerned it may be a risk. I think it remains an unresolved question--can resistance develop after repeated interruptions? If a person has prior drug experience resistant virus is present and can replicate without viral suppression from HAART. A second potentially greater concern is if a person is on a NNRTI regimen and interrupts therapy repeatedly. Nevirapine & efavirenz have long half-lifes. In other words, they stay in the blood for several days after stopping but at decreasing concentrations. So, you are subject to having concentrations at levels not adequate to suppress HIV and the other NRTIs on board have left the body. Data suggests one interruption like this may not be harmful but several repeated interruptions could lead to resistance.

Another risk relates to the one just described related to NNRTIs. A HAART regimen typically contains drugs from 2 or 3 classes--protease inhibitor, NNRTI, NRTI. The pharmacological activity of the 3 classes differ and as well within each class you may have differences between specific drugs. For example, a poster at Durban showed that ritonavir & indinavir increased plasma and intracellular drug levels for d4T. Aside from other implications related to lipodystrophy and dosing, this could mean that after stopping RTV or IDV you could have residual d4T or a different NRTI active at lower or decreasing levels after RTV or IDV have been eliminated. Does this mean that a person could get NRTI resistance? We don't know. How does a NNRTI affect intracellular NRTI drug levels? We don't know. In general, different drugs may be eliminated from the body at different rates. And this may be related to the differing pharmacological activity of different drugs. Questions such as these may be relevant but we don't have many answers. We know many antiretroviral drugs affect each other pharmacologically. Amprenavir increases AZT levels. NNRTIs can sigignificantly reduce PI levels. And a PI often times affects blood levels of HIV drugs as well as other types of drugs. So, when stopping a multiple drug regimen all at once, can we predict with certainty the affect after we've conducted multiple interruptions, sometimes with detectable viral load and with drug resistance?

Some studies of persons with undetectable HIV before the interruption have shown some individuals were not able to get back down to undetectable when restarting therapy. After interrupting therapy viral load increased to a higher level than previously so they couldn't get back to undetectable.

Is there a risk of immune damage or other damage from repeated episodes of viral load depletion & increase?

And as mentioned above, after interrupting therapy CD4s can decrease substantially. An unofficial rule of thumb amongst some doctors is to expect a decline in 33%. So if a person's CD4s are 400 they could decline to 270 or more after interrupting. At what level do you put yourself at risk for an OI or PCP? Another risk is the expected increase in viral load after interrupting therapy. After depleting virus, replication will begin anew in the blood and also in the lymph nodes and other reservoirs. What is the long term affect of "re-seeding" reservoirs with HIV? If conducting multiple sequential interruptions, what is the long term affect of alternately reducing & then starting relpication in the blood, reservoirs, tissues, etc. We don't know. A number of doctors will say they don't think its a risk, that so far it doesn't seem to be a risk. But, we really don't know the potential long term affects.

Stimulating Immune Control With Immune Based Therapies

Still in research is the possibility that using an immune based therapy such as a therapeutic vaccine may stimulate control of HIV with or without HAART. Remune is a therapeutic vaccine and there are several others in research including one from Merck. These vaccines will be used to stimulate control of HIV either with HAART or during therapy interruptions. Studies are in place now taking a look at this possibility. IL-2 is also an immune based therapy that increases CD4 counts. Sometimes severe side effects may accompany IL-2 administration, so it can be difficult to tolerate.. Another concern about IL-2 is that there is concern that the CD4 increases it causes may not be effective in improving the immune system like CD4 increases from HAART. Most people receive good CD4 increases from HAART but not everyone does. In those individuals who do not achieve adequate

CD4 increases but achieve undetectable viral load from HAART they may be candidates for IL-2 therapy. Two large studies are ongoing which will try to unravel whether or not IL-2 CD4 increases really translate into clinical benefit. If the study is successful in identifying benefit, results may not be available for a few years.

A number of studies are looking at supplementing HAART with & without interruptions with a therapeutic vaccine or even combining two therapeutic vaccines with HAART. Studies are also looking at how IL-2 may be used in this mix, possibly in combination with a vaccine & HAART.  One study is planning to look at taking interruptions after increasing CD4s with IL-2, and restarting HAART after CD4s decline following IL-2 increase. But the answers from these studies are not in yet.

THERAPY INTERRUPTION AFTER HAART DUURING ACUTE INFECTION

HIV Pathogenesis and Prospects for Immunotherapy
     Written by Eric Rosenberg,MD. Dr Rosenberg is Instructor of Medicine at Harvard Medical School and Massachusetts General Hospital in Boston.

Topics in HIV Medicine, Vol.8 Issue 6: October 2000 IAS-USA.

This article can be accessed on the front page of the NATAP web site or directly through this link:

http://hivinsite.ucsf.edu/medical/iasusa/3098.0124.html