New Research Findings

Is Human Herpes Type 6 Virus Required for Immune Destruction in AIDS?

The results of one of the more interesting presentations at the 40^th ICAAC suggested that human herpes type 6 may be necessary for lymph tissue destruction in AIDS.  One of the changes that occurs with progressive HIV disease and AIDS is destruction of the normal architecture of lymph tissues, including lymph nodes (glands).  The normal shape and configuration is eventually obliterated (ìwiped outî) and lymphocytes that are normally present are gone.  This is associated with a decline in the CD4 count in blood.  HAART (highly active antiretroviral therapy) reverses the abnormalities, although not always to a normal state.  The specific cause of lymph tissue destruction was thought to be HIV, but the specifics had not been clarified. Now, researchers from the Institute for Viral Pathogenesis in Milwaukee, Wisconsin have suggested that infection and activation of human herpes virus type 6 (HHV6) might be the cause of lymph tissue destruction in AIDS.  HHV6 previously has been associated with ìroseola,î a common infection of young children with rash and fever, some types of seizures (convulsions) with fever in children and specific disease in patients with organ transplants.

Konstance Kehl Knox, PhD examined the density of immune cells infected with HHV6 in lymph glands from two groups of AIDS patients: 12 who had progressive HIV disease and 4 who had stable HIV disease.  Dr. Knox found that all 16 patients had active infection with HHV6 in their lymph nodes.  However, the concentration or density of infected cells was much higher among those with progressive disease than those without it.  And, there was an ìinverse relationshipî between the blood CD4 count and the density of HHV6 infection in lymph nodes.  That is, a lower CD4 count was associated with a higher HHV6 density and a higher CD4 count was associated with a lower HHV6 density.  Also, those areas of the lymph nodes with the highest density of HHV6 had the lowest density of lymphocytes (ìlymphocyte depletionî).  Dr. Knox concluded that HHV6 ìis the cause of the lymphoid tissue destruction that occurs in patients infected with HIV, probably through a synergistic [enhanced effect by combining] interaction between it and HIV.î Dr. Knox hypothesizes that specific antiviral treatment for HHV6 in patients with HIV infection might decrease the rate of lymph tissue destruction.

One of the problems with the study is the classic ìchicken and eggî discussion.  It is possible that as the CD4 count decreases, this allows for activation of HHV6 (and many other ìopportunisticî infections in AIDS).  So the question is which comes firstóCD4 cell depletion or HHV6 reactivation?  Dr. Knox did not necessarily prove that HHV6 is the cause of CD4 depletionóit may merely be associated with it and could actually be the result of it.  Either way, the report was interesting and might add to our knowledge as to what causes HIV disease progression and associated destruction of lymph node architecture.  Regardless, effective HAART can reverse the lymph tissue destruction, at least partially.

Reference
Knox KK and others.  Active infection by variant A of human herpesvirus six causes destruction of lymphoid tissues of HIV infected individuals.  Abstract and poster 787.

Many patients are taking low-dose (ìbabyî dose) ritonavir (Norvir) to boost the blood level of a second PI (protease inhibitor) drug.  One concern physicians have had about using low-dose ritonavir is whether this could possibly lead to developing ritonavir resistance mutationsóand possibly cross-resistance to the second PI drug.  Or, that developing ritonavir resistance mutations might start someone down the ìslippery slopeî of developing other PI drug mutations and eventual HIV viral ìbreakthroughî (rebound).  A significant concern would be if the second PI drug were indinavir (Crixivan), since ritonavir and indinavir share ìgenotype resistance mutations.î  The most common argument against this concern is that if complete viral suppression (undetectable viral load) occurs due to successful HAART (highly active antiretroviral therapy), no HIV will reproduce and no resistance mutations would develop.  However, Diane Havlir, MD of the University of California at San Diego and others have reported that viral ìblipsî commonly occur, even with an ìundetectableî viral load due to HAART.  And, we do not know whether all HAART medications penetrate every compartment and every cell in the body.  And that assumes 100% adherence to drug dosing.

(Editorial comment from Jules Levin: Diane Havlir reported that individuals she studied from ACTG 343 (IDV+AZT+3TC who were treatment naÔve) did not fail therapy despite low level viral blips after following them for 5 years. This was reported at the Resistance Workship Summer 2000. You can read reports on the NATAP web site).

Now, S. Chaillou, MD from Nice University Hospital in France has reported that ritonavir resistance mutations have developed in HIV patients taking low-dose ritonavir with saquinavir (Fortovase) combination ìsalvageî therapy.  Patients were a part of the ìVIRADAPTî ìgenotypeî resistance study.  There were 34 patients in that study who were switched to low-dose ritonavir (100 mg twice daily) plus saquinavir combination therapy.  Among those patients, genotype resistance to ritonavir developed in some during the next 12 months.  The ìV82A/F/Tî ritonavir mutation developed in 23% and the ìM46I/Lî ritonavir mutation developed in 15%.  The researchers also measured the lowest (ìtroughî) blood levels of ritonavir.  The results were a median (average) concentration of 0.47 micrograms per milliliter.  This is not far from the ìEC₅₀î (effective concentration that inhibits 50% of wild-type HIV, without mutations) of ritonavir.  The authors conclude that low-dose ritonavir ìcould be a threat in naÔve [no previous treatment] patients as it could select ritonavir/indinavir resistance associated mutations.î  And, those ìcould be added to the specific resistance associated mutations of the boosted PI [drug].î  Potential ìconfoundingî factors in the study include other baseline PI drug mutations (all had a previous PI drug regimen that led to viral rebound), dosing adherence and the long-term significance (long-term viral load suppression).  Until the findings and significance of this report are confirmed (or not) in other studies, patients should not stop or change their anti-HIV medications without talking with their physician first.

(Editorial comment: It's worth repeating that as stated above patients in this study had prior PI exposure which could be related to RTV mutations being seen in this study. It may be important to distinguish between using 100 or 200 mg of RTV as a booster of the drug level of a second PI from using 400 mg of RTV in combination with a second PI. In speaking with several researchers about this study they felt the study was flawed because patients had prior PI experience. I think the general feeling is that low levels of RTV used as a booster (100 or 200 mg) should not lead to RTV resistance but it appears that there are no definitive studies on this). When using 400 mg of RTV, surely resistance can develop.

Reference
Chaillou S and others.  Does ritonavir ìbaby doseî induce specific mutations in salvage combination therapy? A VIRADAPT sub-study.  Abstract and poster 1267.

Bone Mineral Loss (Osteopenia, Osteoporosis) Found in HIV Patients Who Never Took Anti-HIV Drugs

Two studies at this yearís 7^th Retrovirus Conference suggested that loss of bone minerals (osteopenia, osteoporosis) was associated with PI (protease inhibitor) drug therapy.  And, the reports concluded that it was very common in HIV patients taking HAART (highly active antiretroviral therapy).  Now, researchers from Hospital Hotel-Dieu in Nantes, France have reported that bone mineral loss occurs in HIV positive patients, even without any treatment for HIV.  E. Billaud, MD, the lead author also reported that bone mineral loss was associated with the total time of HIV infection and not with the presence of ìlipodystrophyî (fat redistribution).  Severe bone mineral loss increases the risk of bone fractures.

A total of 85 HIV positive patients were included, with 18% women and 3% Blacks.  Bone mineral density was measured by ìDEXAî (ìdual energy X-ray absorptiometryî) testing.  Definitions for ìosteopeniaî and ìosteoporosisî (severe loss of bone mineral density or concentration) were similar to those used by the World Health Organization.  Among the 15 patients who never took any drugs to treat HIV, 20% had ìosteopenia.î   Among the patients taking combination therapy to treat HIV, osteopenia was present in 40% of those taking a PI drug and 45% of those not taking a PI drug.  Severe bone mineral loss (osteoporosis) was present in none of those who had not taken anti-HIV therapy and in 7% of those who were.  In a ìunivariate statistical analysis,î factors associated with bone mineral loss included total length of HIV infection, daily calcium intake, and ìosteocalcineî levels (marker of bone formation). 

The authors concluded, ìOsteopenia and osteoporosis are more frequent in patients with prolonged duration of HIV infection with no clear association with use of potent ART [antiretroviral therapy].î  The study results would need to be confirmed in larger studies.  Regardless of the cause (HIV and/or ART), patients may ultimately need specific treatment for bone mineral loss.  Limitations of the study include a small number of patients, other factors among the women that might have contributed to bone mineral loss and no ìmultivariate statisticalî analysis.

(Editorial comment: additional studies on this subject were reported at ICAAC and the Lipodystrophy Workshop in Toronto. Reports can be read on NATAP web site, here is direct link to article: Review of Studies on Bone Problems at ICAAC and Lipodystrophy Workshop)

References
Billaud E and others.  Osteopenia and osteoporosis in HIV-infected patients: role of antiretroviral therapy? Abstract and poster 1304.

Hoy J and others.  Osteopenia in a randomized, multicenter study of protease inhibitor substitution in patients with the lipodystrophy syndrome and well-controlled HIV viremia.  Abstract 208 at the 7^th Conference on Retroviruses and Opportunistic Infections; January 30-February 2, 2000; San Francisco, California.

Tebas P and others.  Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy.  Abstract 207 at the 7^th Conference on Retroviruses and Opportunistic Infections; January 30-February 2, 2000; San Francisco, California.