Report 3

Safety of STIs: 3TC resistance and HIV reservoirs

Cecile Tremblay (Mass General Hospital) discussed at the Workshop (abstract 19) whether a STI (Treatment Interruption) can contribute to the replenishment of HIV reservoirs and is there resistance when viral load rebounds following an STI. Can STIs foster the emergence of resistance. She

reported on 14 individuals treated during acute infection. It’s important to bear in mind that these patients started treatment during acute infection. Levels of infectious virus (infectious units per million cells, IUPM) were computed at time points before and after STIs. It’Äôs also important to bear in mind the researchers (The Walker Group at Mass General) used sophisticated lab methods to measure infectious virus. Tremblay reported there was no increase in the level of infectious virus recovered from CD8 PBMCs following an STI in the 7 studied patients.

One of 14 subjects had a 3TC 184 mutation detected for the first time after start of first STI. HIV was re-suppressed when 3TC was restarted along with other drugs, but 184 re-emerged at next STI. In two subjects in total, rebounding virus showed some evidence of viral evolution (resistance) from the 1st to 2nd STI. This study raises a concern about the safety of STIs regarding resistance. The emergence of 3TC resistance could be because of the longer intracellular halflife of 3TC, which raises concerns about efavirenz and nevirapine which also have long halflifes.

This is a preliminary study which does not address safety issues of STIs very well, but raises concerns about resistance.

Joep Lange, MD (National AIDS Therapy Evaluation Centre, University of Amsterdam) was a guest of my radio show today (recorded for this Sunday 6/17) where we talked about this study and its implications, and treatment interruptions in general. This study was conducted in persons treated during acute infection when the suppressive power of the immune system is greatest.

Therefore, Lange feels the fact that the HIV reservoir in latent reservoirs was not found to increase may not apply to individuals in chronic infection. He thinks this remains an unanswered question: whether HIV increases during treatment interruption in acute infection will increase the latest reservoir as well. Regarding the issue of 3TC resistance, he felt this was a previously overlooked issue because 3TC has a long halflife in the cell not necessarily in the blood, so it did not receive much attention. He said resistance to 3TC and NNRTIs can be a concern when stopping therapy.

We already knew that if a person was on nevirapine or efavirenz (NNRTIs) that if you stop a regimen, blood levels for those drugs decrease more slowly and drug remains in blood at decreasing levels for a couple of days, at levels not capable of fully suppressing HIV. Thus, resistance to the NNRTI may develop. But this finding regarding 3TC is something that appears to have been overlooked. Regarding protease inhibitors, he feels the potential for resistance to a PI after stopping therapy can also be a concern but is not yet an answered question so we don’t know.

In theory, you would not expect a PI to create a resistance issue because of the short halflife of a PI, but its possible other factors may be involved. We talked about the fact that a number of studies looking at interruptions have not found resistance to drugs. He said the reason may be because the studies did not use sophisticated methods to look at reservoirs but only looked for resistance in a surface way. He feels that taking a treatment interruption may subject the patient to risks that we are not familiar with yet. For the patient with well suppressed HIV and not having a serious problem with toxicities & side effects, but is just tired of taking their pills, he recommends against treatment interruptions. He says the risks are unknown and not worth it. Many studies are ongoing trying to evaluate if these risks are real.

TDM (Therapeutic Drug Monitoring)

We talked about TDM and Lange feels that using drug blood level testing is the future in HIV. In Amsterdam, HIV clinics have pharmacology staff that review all patients regarding blood levels. In France, this is done more routinely as well, than in the US. Here in the US, doctors for the most part have not picked up on using TDM, although a few docs here and there use it.

Lange firmly believes that regularly testing blood levels including soon after a patient starts a regimen provides crucial information on whether the patient is adherent and whether the patient is achieving adequate drug blood levels. A doctor can access drug blood level testing through various labs here in the US, you can ask your doctor about it.

Lange talked about the ATHENA study, which is the first prospective study finding that testing drug blood levels improved treatment outcome. This study was presented at the Pharmacology Workshop in April in the Netherlands. You can read the NATAP Report on Athena at:
http://www.natap.org/2001/2ndworkshop/1bartnof041001.htm

You can read the entire NATAP Report on the Pharmacology Workshop at:
http://www.natap.org/2001/2ndworkshop/2ndwrkshopindex.htm

In the Athena study, the use of nelfinavir and indinavir regimens were reported. Lange said and the data reported showed that using TDM improved improved outcome (percent undetectable). For individuals using a nelfinavir regimen, nelfinavir levels in the blood were monitored. This allowed to check for patient adherence and nelfinavir levels that could have been too high or too low. The problem that emerged with nelfinavir was that levels could be too low, and often that could be improved when patients were reminded to eat adequate meals when taking nelfinavir. He said patients often did not eat properly. If changes in diet did not improve nelfinavir blood levels, the second step was to increase the dose. And if this did not work the third step was to boost nelfinavir levels with ritonavir.

The Athena study found that the problem emerging regarding indinavir was drug levels that were too high. Patients could be experiencing high IDV blood levels and consequent toxicities, and therefore may not have been taking IDV. They may not have been adherent due to side effects & toxicities. When dosing of IDV was reduced side effects & toxicities declined and outcomes improved.

The study found that patients improved in terms of the percent undetectable on NFV and IDV after these steps were taken.

The radio interview was recorded for the weekly NATAP radio show "Living Well With HIV & Hepatitis" which is on WOR 710 AM in New York City every Sunday 11pm to 12 Midnight. The Lange interview will be on the air this Sunday June 17. Free recorded cassettes are available for all our shows and can be ordered on the NATAP web site at www.natap.org or by contacting NATAP (888-26-natap; 212 219-0106; info@natap.org

Viral "Blips"

Lange and I discussed this study-- Lisa Frenkel (abstract 27) and her group from the University of Washington Seattle reported on a child on HAART with 8 viral blips of between 50-101. Over the course of 5 years the child had 11 viral load tests of <50 copies/ml and 8 tests reported blips between 50-100.

This patient developed new mutations in PBMCs (cells). This was compared to one child who had one blip of 104 copies/ml during 4 years of effective HAART. The "blipper" was intensified with a more potent regimen of 4 drugs. The premise of Frenkel, although this is a very small study, is that more potent HAART may be required for many patients to keep viral load <50, and the goal of therapy should be to keep viral load <50. She suggests that resistance and subsequent viral failure will occur as a result of blips and resistance.

Lange feels that consistent blips even at this low level (50-100 copies/ml) may lead to resistance and develop into viral failure. Other researchers may disagree. Diane Havlir (UC San Diego) has reported from a small study that low level blips such as this did not turn into failure but the study was limited in time of follow-up (I think it was 2 years). At the Retrovirus Conference 2001, a high profile study reported that several consecutive low level viral load rebounds of several hundred copies/ml was more likely to turn into viral load rebound. There is some controversy surrounding whether or not low level blips leads to eventual viral load failure, but intensifying treatment when there are consistent blips of 50-100 may be the safest approach until this question receives more research attention.