Medical Consultant
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6th Conference on Retroviruses and Opportunistic Infections
ISSUE 65 - Conference Report Special
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OTHER NEWS
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6th Conference on Retroviruses and Opportunistic Infections
January 31 - February 4, 1999 - Chicago, IL
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Dr Emilio Ledesma, FIT (Formaci(n e Informaci(n sobre Tratamientos en el VIH/SIDA), Madrid. Antiretroviral resistance has been long identified as a major "Achilles heel" of HIV treatment. Now, resistance is a subspeciality in HIV research, and the Chicago conference included much additional information on the more debated issues of the resistance field:
The GART (Genotypic Antiretroviral Resistance Testing) trial was presented as a late breaker by J.D. Baxter, MD, from the Community Programs for Clinical Research in AIDS 046 Study Team [1]. This is the second prospective trial comparing standard therapy versus genotypic resistance test guided treatment (see ATP's "DocFax" Issue 58 for a report on the VIRADAPT study). GART included 153 patients who had experienced virologic failure (viral load increase >3 fold) while receiving combination treatment with 2 nucleoside analogues (NA's) plus a protease inhibitor (PI). Patients where randomly assigned to receive genotypic testing (GART) (n=78) or no-GART (n=75). At baseline, mean CD4 counts was approximately 230 cells/L, and median viral load was just over 25,000 copies/mL. Baseline failing regimen for half of the patients was the second they had received containing a PI.
Lamivudine high level resistance mutation M184V was present in 82% of the patients at baseline, and 61% had the landmark mutation of ZDV resistance, 215F/Y. Mutations both in the protease and the reverse transcriptase genes were observed in 73.2% of the patients. The most frequent protease mutations were at codon 82, 90 and 46. A virologic panel reviewed the genotypic resistance test results for the GART group (PE Biosystems system), and provided recommendations to the physicians.
| GART | NO GART | |
| VL | -1.17 | -0.62 * |
| <500 copies/mL | 29% | 17% |
*p=0.0001
Evidence of viral loads moving back towards baseline was seen in both groups at 12 weeks. On subsequent analysis it was found that patients in the GART group had more active drugs prescribed than people in no-GART (hardly surprising as this is exactly what access to genotyping should ensure!).
Genotype results were interpreted by a virologist but physicians were not mandated to follow the virologists advice. An analysis was therefore performed to measure the effect of the clinicians adherence to the virologists recommendations on which antiretrovirals to use for each particular patient. Study sites that followed the recommendations in more than 80% of the patients saw a median viral load drop of -1.4 log in the GART arm, versus a -0.47 log drop in the NO GART control arm at these same sites. In contrast, sites that followed the advice for less than 60% of the patients saw a median -0.98 log drop in the GART arm, and a -0.74 log drop on the no-GART arm.
The main conclusion of the GART study was that "...GART with expert advice in patients failing antiretroviral therapy was superior to no-GART, as measured by short-term viral load responses. The greater viral load reduction with GART is attributed to a greater number of active drug prescribed. The effect of GART on viral load response may be underestimated as treatment suggestions were not followed for all patients".
A brief report of the ACTG 244/RV79 trial in which patients were randomised according to their 215 wild type or mutant status, indicated that, as long known, the 215Y/F mutation selected during ZDV monotherapy carried a bad prognosis (decrease CD4 counts in this study). This effect on prognosis was irrespective of subsequent therapies received (ZDV/ddI, ZDV/ddI/nevirapine). After changing therapies CD4 counts declined in those patients with mutant 215 whilst those with wild type 215 increased their CD4 counts. The poor response seen in those with the zidovudine associated resistance mutation T215Y/F was out of proportion to that expected from reported levels of cross resistance [2].
As a result of the increasing number of HIV-infected people receiving treatment and carrying resistant mutant viruses, a certain number of people who are yet to receive treatment are harbouring resistant viruses. These patients have not seen drugs before, but their viruses did before being transmitted to their new host.
Sero-surveillance of this phenomenon, known as primary resistance, is important for both therapeutic strategy design and public health reasons. According to John Mellors, member of the IAS-USA Resistance Panel guidelines, primary resistance rates over 10% should prompt a change in antiretroviral prescription policies, at least in those places where drug resistance testing is not available [3]. The research presented at the Chicago conference suggested that, while the prevalence of primary resistance to individual drugs may not be increasing, the phenomenon is broadening its limits, now affecting all three major classes of antiretroviral drugs.
In Spain, the second surveillance study, ERASE-2, did reveal an overall HIV resistant population of over 60% (mainly ZDV and 3TC resistance mutations), using the LiPA assay complemented with the developing protease gene LiPA and some point mutation assays for the multinucleoside resistance mutations/inserts [4]. The results presented in Chicago mentioned an overall prevalence of RT resistance in drug-naive patients of 12% in 1997, mainly ZDV resistance, although for the recent seroconvertors, 3TC resistance was the most common observation [5].
In a study performed by Virco using their VircoGENTM and AntivirogramTM systems, 21% of the 114 analysed samples from recent (up to 3 years) infections had evidence (either geno or phenotypic) of resistance to at least one antiretroviral [6]. By genotyping, 2.1% of samples had evidence of resistance to all three classes of available drugs. This figure rose to 3.2% when assessed with the phenotyping method. Interestingly the drug class with the highest incidence of resistance was the non-nucleoside reverse transcriptase inhibitor (NNRTI) with 15% and 23% of drug na•ve recent seroconverters harbouring NNRTI resistant virus by the genotypic and phenotypic testing methods respectively. Similar results were communicated by Little et al, from a study using the ViroLogic phenotypic assay in 5 centres in the US [7]. 69 patients were assessed who had documented seroconversion in the previous year (samples drawn a median of 55 days after seroconversion). Resistance to any drug was documented in 28% of the samples. Just 3% of the participants had nRTI primary resistance, but as many as 17% showed resistance to non-nucleosides, and 13% showed protease resistance (2 subjects had phenotypic resistance to all 4 anti-protease drugs).
Resistance profiles of new drugs have become a major point of interest, particularly now that regulatory authorities take resistance profiles very much into account when deciding the speed of approval of a new compound. Adefovir, abacavir and some new non-nucleosides in the RT inhibitor group and some phase II/III protease inhibitors attracted much of the attention.
Adefovir is a nucleotide analogue under development by Gilead Sciences. Although not intrinsically very potent, it is active against all the nRTI resistance strains tested (even the Q151M multidrug resistance mutation complex), and it may even have a special activity against M184V carrier viruses [8]. While not well genotypically characterised yet, phenotypic resistance greater than 5-fold was correlated to poor response to adefovir in the GS-408 trial [9].
Abacavir is a nucleoside analogue currently commercially available in the United States. Its resistance profile is the focus of a lot of research, as while sharing resistance mutations with most of the nucleosides (3TC, ddI, ddC), and being affected by ZDV resistance mutations, its step-wise resistance acquisition make it an active drug in certain nucleoside-experienced patients [10]. While the Q151M multidrug resistance complex confers full resistance to abacavir, those patients with the 184V RT mutation only do not have great enough resistance to abacavir as to preclude its activity [11, 12]. When the nucleoside mutation load increases to greater than 2 point mutations in the reverse transcriptase gene abacavir efficacy is hampered. No data on the impact of the 69 double inserts on abacavir activity was presented at Chicago, but previous data shows that abacavir is inactive in its presence.
Efavirenz, the latest non-nucleoside being incorporated into clinical practice, shows class cross-resistance. In vitro, "only" a 17-fold increase of IC50 is conferred by the K103N, and a 24-fold increase is seen with the L100I mutation. When combined though, resistance increases to a full 2300-fold increase of the IC50 [13]. When assessing new NNRTI's in development such as DPC 961 and 963 or Glaxo's GW420867X (known as "867") or MK462, critical attention must be given to their activity against these double mutant NNRTI resistant viruses.
Amprenavir is a protease inhibitor under development by GlaxoWellcome. Though initial reports did suggest an absence of cross-resistance to the other PIs, we now know that common PI resistance mutations such as those at codons 84 and 10 are the more potent predictors of amprenavir resistance [14].
ABT378 is a new protease inhibitor to be co-formulated with low doses of ritonavir to enhance the blood levels of ABT378. There are no in vivo data on resistance to this compound, but in vitro assays indicate at least two resistance pathways, through the primary mutations at codon 84 or 50 [15]. The very favourable pharmacokinetic profile of this drug will play a potent protective role against resistance, as levels well above the IC50 values of resistance strains are easily achieved.
BMS232,632 is an azapeptide HIV-1 protease inhibitor under development by Bristol-Myers Squibb. Scarce in vitro data on this new protease just entering phase II show partial cross-resistance to other protease inhibitors, although data presented at Chicago seemed to suggest monodirectional cross-resistance yet to be clarified [16].
A poster reported on the selection of classical zidovudine resistant mutants in a group of people treated with d4T+ddI and without prior ZDV resistance [17]. Out of the 26 isolates, seven had either the T215Y/F or the M41L or the D67N mutation, the Q151M mutation having developed in 2 patients. The interpretation of these data in light of current triple or quadruple combination therapy needs to be addressed.
The P157S confers moderate-low resistance to 3TC, as described by R Smith et al. While searching for a HIV correlate of the P156S of the FIV, which confers high level dual resistance to ZDV and 3TC, researchers at Utah and California described in vitro the P157S mutant strain, which shows a 5-fold decrease in the 3TC IC50. This mutation was observed at least in one human HIV isolate [18].
A collaborative study between the Gladstone Institute of Virology and Immunology in San Francisco and Dr Clavel's lab at the Hop. Bichat-Claude Bernard in Paris described a selective lack of fitness of protease resistant viruses. Using a SCID-hu Thy-Liv mouse model and pre- and post-therapy protease genes from patients in NL4-3 recombinant clones [19]. The researchers measured the fitness of the viruses in human thymic cells. Pretherapy protease carrying virus could replicate normally, as measured by p24 production and cell depletion. Surprisingly, resistant protease carrying viruses from post-treatment patients could not replicate in the thymic cells. This decreased thymic fitness of protease resistant viruses could well be a mechanism by which a certain percentage of protease-failing patients who maintain protease treatment do not lose CD4 cells at the expected high viral load-driven pace.
References: 1. Baxter JD, Mayers DL, Wentworth DN, et al: A pilot study of the short-term effects of antiretroviral management based on plasma genotypic antiretroviral resistance testing (GART) in Patients failing antiretroviral treatment [Abstract LB8]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
2. Mayers D, Merigan T, Gilbert P, et al: T215Y/F mutation associated with zidovudine (ZDV) resistance leads to poor response to ZDV+ddI or ZDV+ddI+NVP: ACTG244/RV79 [Abstract 129]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
3. Antiretroviral Drug Resistance Testing in Adults with HIV Infection. Hirsch et al. JAMA, June 24, 1998;279:1984-1991.
4. ATP-Doctor Fax Symposium Report, Drug Resistance Testing in HIV Clinical Care. Oct 22nd, 1998.
5. Gomez-Cano M, Rubio A, Puig T, et al: Prevalence of drug resistance mutations over time in naive HIV+ subjects living in Spain [Abstract 125].
6. Wegner S, Mascola J, Barille A, et al: High frequency of antiretroviral drug resistance in HIV-1 from recently infected therapy na•ve individuals. [Abstract LB9]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
7. Little S, Daar E, Keiser P, et al: The spectrum and frequency of reduced antiretroviral drug susceptibility with primary HIV infection in the United States [LB10]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
8. Anton KE, Miller MD: Adefovir and PMPA are active in vitro against HIV from patients with multiple patterns of nucleoside resistance mutations and the lamivudine-associated M184V RT mutation [Abstract 124]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
9. Miller MD, Anton KE, Margot, et al: Response to therapy with adefovir dipivoxil is durable for 48 weeks and correlates with baseline HIV genotype and in vitro susceptibility to adefovir [Abstract 137]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
10. Van Laethem K, Witvrouw M, Schmit J-C, et al: The multiple nucleoside analogue resistance mutations confer cross-resistance to abacavir [Abstract 113]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
11. Henry K, Shaeffer M, Ross L, et al: Response to Combivir_ and abacavir given BID to nucleoside experienced patients is not affected by the presence of the M184V mutation [Abstract 132].
12. Ait-Khaled M, Stone C, Mesogiti D, et al: Genotype and phenotype of HIV-1 in ART experienced adults prior and following therapy with Ziagen (abacavir, ABC) added to stable background therapy [Abstract 114]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
13. Jeffrey S, Corbett J, Bacheler L: In vitro NNRTI resistance of recombinant HIV carrying mutations observed in efavirenz treatment failures [Abstract 110]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
14. Tisdale M, Myers RE, Ait-Khaled M, et al: HIV drug resistance analysis during clinical studies with the protease inhibitor amprenavir [Abstract 118].
15. Mo H, Chernyavskiy T, Lu L. et al: Multiple pathways to resistance to ABT-378 observed by in vitro selection [Abstract 117]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
16. Gong Y, Robinson B, Rose R, et al: Resistance profile and drug combination studies of HIV-1 protease inhibitor BMS-232632 [Abstract 603]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
17. Coakley E, Gillis J, Hammer S, et al: Mutations in the reverse transcriptase genome of HIV-1 isolates derived from subjects treated with didanosine and stavudine in combination [Abstract 116].
18. Smith R, Klarmann G, Stray K, et al: A new point mutation in HIV-1 RT confers resistance to 3TC in vitro [Abstract 126]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
19. Stoddard C, Mammano F, Moreno M, et al: Lack of fitness of protease inhibitor-resistant HIV-1 in vivo [Abstract 4]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
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The studies GART and Viradapt, although hinting at the potentials of resistance testing, are disappointing in that benefits are small (around -0.5 log VL) and there appears to be some loss of benefit at later time points. This may reflect the heavily pretreated nature of patients and in Viradapt the high baseline viral loads. The consistency of 215 mutant RT gene and poor prognosis is concerning, especially as it now appears that d4T also selects for this mutation. One might ask if the era of thymidine analogue sparing is upon us, excepting the unforeseen consequences of extensive use of other base nucleoside analogues. |
When HIV is well controlled with antiretroviral drugs, immunity to infections-other than HIV-usually starts to return. As a result, some opportunistic infections go away without specific treatment; and sometimes patients can stop prophylactic treatment for certain opportunistic diseases (although today it is often unclear who can stop prophylaxis safely, and who cannot).
But immunity to HIV itself is different. The CD4 T-helper cell response to HIV usually appears to be eliminated very early in HIV infection, and to return very slowly or not at all, even when HIV has been well suppressed for years with antiretrovirals, and other immunities do return. And without this helper response, the HIV-specific CD8 CTLs (cytotoxic T lymphocytes), which appear to be centrally important to the control of the virus during the initial HIV infection (primary HIV disease), seem to lose their ability to respond effectively to chronic HIV infection.
No one knows for sure why HIV is different from other viruses in this way, but it is likely that because HIV specifically targets activated CD4 T-helper cells, it will selectively kill especially those cells which are able to recognise it and respond. And when HIV is not present due to being suppressed by antiretrovirals, the CD4 T-helper cells genetically able to recognise it usually do not respond- possibly because they were wiped out earlier, or because they were damaged in some way, or simply because they will not encounter HIV antigens, and therefore not become activated and not mobilise normal immune responses.
The potential importance of the body's failure to restore HIV-specific immunity becomes clear when one realises that long-term nonprogressors-the small minority of persons who are infected with HIV but naturally maintain a very low viral load, with a high CD4 count and no evidence of disease progression even after many years-usually do have a CD4 T-helper cell immune response to HIV, while those who progress and become ill invariably do not. If HIV-specific immunity could be restored, might persons who now have HIV disease become long-term nonprogressors, no longer needing any treatment, or perhaps only needing treatment occasionally if their immune system begins to lose control of the virus again? No one knows at this time, since the research is just beginning. But the results so far are promising, and a handful of patients who had been dependent on antiretrovirals have already been able to stop these drugs entirely, sometimes for more than a year, without having the viral-load rebound that almost always happens when patients stop their antiretroviral treatment (and which did happen to these individuals when they first tried discontinuing their antiretrovirals).
Administering HIV antigens or whole killed virus while the host virus is well suppressed with antiretrovirals is a potential strategy to induce immunity. In one study, first reported last summer at Geneva and with new data last week at the Retroviruses conference, volunteers whose viral load had been effectively suppressed with antiretrovirals were also given a killed-virus immunogen (the Remune(tm) therapeutic vaccine, which was developed by the late Dr. Jonas Salk); a control group was given the inactive component of the same vaccine but without the HIV. T-helper responses like those of long-term nonprogressors returned in most of those given the real vaccine-and in none of the control group (see details below).
It is not known that producing an immune response in this way will have clinical benefit, since the results so far have been only laboratory tests, as none of these volunteers has yet chosen to stop their drugs in order to see whether or not their viral load comes back.
Here is one theory of what may be happening in this case. As a person's CD4 count increases after suppression of HIV by antiretroviral drugs, a few of the cells that make up that count are new, "naive" CD4 T-helper cells released by the thymus (naive T-cells are those which have not yet encountered the particular antigen-such as a protein from a particular virus or bacterium-which the cell is genetically programmed to recognise). Of these new naive cells, a small minority are, by chance, programmed to recognise HIV. Without the antiretrovirals, these cells would recognise HIV, become activated as they started to respond to it, but then be destroyed by the virus. With only the antiretrovirals, the cells would be protected from infection, but there would be so little HIV present that they would not encounter it and not create an immune response. Adding the vaccine which is made from killed virus apparently allows these cells to safely develop a normal immune response.
It is also noteworthy that the killed-virus vaccine used in this test is made from a virus from Africa which is not clade B-the variant of HIV which is common in the U.S. and Europe. Even so, the volunteers in this small trial did develop immune responses to purified HIV p-24 antigen from two different clade B viruses, as well as to the immunogen itself-indicating that this approach might be able to confer a broad protection against many forms of HIV, not limited only to the particular kind of virus which was used to prepare the therapeutic vaccine.
Incidentally, the developers of Remune-the Immune Response Corporation, later acquired by Agouron Pharmaceuticals- prefer to call this product an 'immunogen' rather than a 'vaccine'. It is currently being tested in a large phase III trial, separate from the small 43-person trial presented at the Retroviruses conference; data from the phase III study will be available later this year. Remune has never been tested in an HIV-negative person, as a potential preventive vaccine; some experts believe that it should be tested for this purpose.
The therapeutic vaccination trial outlined above was presented by Fred Valentine, M.D., of New York University. A total of 43 patients were treated with highly active antiretroviral therapy (HAART), and were randomly assigned the Remune immunogen (a vaccine made from killed HIV) or a placebo (in this case the placebo was IFA, which is an adjuvant-a substance used to make a vaccine work better- used in the Remune immunogen). The injections were given at weeks 4, 16, and 28. At week 32, the group receiving the immunogen had a much higher CD4 T-helper response to three different HIV antigens, and a higher production of MIP-1-beta in response to HIV antigen; statistical significance for these four measures was very good, from p=0.007 to p=0.0002 (levels reported in the published abstract). Also, there was a trend toward lower viral load, but it did not reach the p=0.05 level usually taken as statistically significant (p=0.29 and p=0.09 in the abstract, p=0.07 currently). Unfortunately recruitment for this study was cut short over a year ago, before its importance was known, due to financial constraints; if the trial had been fully enrolled, it might have already shown statistical significance for viral load reduction. Note also that statistical proof of viral load effect is hard to prove in this case, simply because both groups did so well.
It is important to note that the volunteers in this trial were not treated during or near primary infection, but could have been infected at any time. They were treatment naive and had a median CD4 count of 493 and a median viral load of about 8,000 copies before they began the study-not because this approach could not be made to work for more advanced patients, but because it made sense to try the first proof-of-principle study in volunteers who had less immune damage and were easier to treat.
It is also important to remember that there is no proof yet that producing HIV-specific immunity will benefit patients - since it is possible that long-term nonprogressors are able to resist HIV infection through some other mechanism, and that their HIV-specific immune responses are a consequence of that, not the cause of their remaining well. But the information available today does suggest that HIV-specific immunity is centrally important in the control of this virus.
Ref: Valentine F, DeGruttola V, and the Remune 816 Study Team. Immunological and virological evaluations of the effects of HAART compared to HAART plus an inactivated HIV immunogen after 32 weeks. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, January 31 - February 4, 1999 [abstract #346]. Source: AIDS TREATMENT NEWS #312, February 12, 1999, Published twice monthly. Subscription and Editorial Office: P.O. Box 411256, San Francisco, CA 94141.
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The data on Remune continue to produce excitement and interest. It is difficult, at present, to determine if this is due to the limited evidence of efficacy available so far, or due to anticipated success based on biological plausibility. The contribution to loss of antiviral drug efficacy by the decline in viral suppression by HIV specific host immune factors is unclear, but may be substantial in those with 'long term' potent viral suppression through drug therapy. Remune appears (albeit non-significantly in this small study) to reduce this failure, helping the immune system to act as "our other drug". The question remains if, after rebuilding HIV specific CTL, drugs can be stopped and the person behave as a long term non-progressor? Potential for support of failing drug therapy in those advanced patients with low options furthers the need for compassionate access to this therapeutic vaccine. This amid concerns over the accessibility of Agouron's expanded access programme for Remune in the U.S., a programme that never even got planned for the rest of the world! |
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OTHER NEWS
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Source: CATIE NEWS
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A letter to the BMJ (Aldridge J and Measham F. Sildenafil (Viagra) is used as a recreational drug in England. BMJ 1999;318:669, 6 March 1999 ) identifies the increased availability and abuse of this drug in night clubbers. Viagra, is indeed, widely available "on the streets" and notably, almost exclusively in 100mg tabs (highest dose tablet). Use in combination with protease inhibitors may not only make side-effects more severe, but also more prolonged. There is no need for protease inhibitor users to miss antiviral doses to use Viagra - dosing should start at 25mg. Sensible advice would be to have someone responsible present who will look after them and seek immediate medical attention if side effects occur. |
Using data collected through the U.K. Mycobacterial Resistance Network, researchers examined Mycobacterium tuberculosis resistance levels of newly diagnosed cases in the United Kingdom between 1994 and 1996. They calculated resistance to each first line antibiotic and multidrug resistance, finding that just under 6 percent of over 10,000 isolates were found to be resistant to isoniazid, while 1.7 percent of isolates were resistant to rifampicin, 1.2 percent to pyrazinamide, and 0.7 percent were resistant to ethambutol. Multidrug resistance was observed in 1.5 percent of isolates. Multidrug and isoniazid resistance rates were found to be higher in people aged 15 to 44 years, people with a known history of tuberculosis, males, and patients co-infected with HIV. Patients from England--particularly London--were also found to have higher rates of isoniazid and multidrug resistance, compared to patients from elsewhere in the United Kingdom. The scientists note that, although overall resistance is low in the United Kingdom, it is important to maintain surveillance of the disease.
Ref: British Medical Journal Online (02/20/99) Vol. 318, No. 7182, P. 497; Irish, Charles; Herbert, Josephine; Bennett, Diane; et al. Source: CDC HIV/STD/TB Prevention News Update
Dr. Patrick Chariot and other researchers from Creteil, France, comment on selenium deficiencies found in HIV-positive patients who show dilated cardiomyopathy reported by Barbaro et al. in the New England Journal of Medicine. In a letter to the editor, Chariot et al. report a study they conducted to determine whether antioxidant deficiencies may be implicated in cardiac involvement in HIV-infected patients. According to the researchers, selenium and vitamin E deficiency may be involved in the pathogenesis of dilated cardiomyopathy in patients with HIV. In response, Barbaro and associates note that the role of selenium deficiency in the development of HIV-associated dilated cardiomyopathy is still controversial and that Chariot's findings cannot be considered definitive because of the small sample size.
Ref: New England Journal of Medicine (04/03/99) Vol. 340, No. 9, P. 732. Source: CDC HIV/STD/TB Prevention News Update.
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Selenium supplementation as part of a comprehensive nutritional support would seem warranted. Especially in areas with low soil levels of selenium such as the U.K.
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The Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children (U.S.A.) has updated the Guidelines for the Use of Antiretroviral Agents in Paediatric HIV Infection. The updated guidelines were released on March 1, 1999, through the HIV/AIDS Treatment Information Service (ATIS).
The guidelines include new information about the use of efavirenz (Sustiva), a non-nucleoside reverse transcriptase inhibitor (NNRTI), in combination with other antiretroviral agents to treat HIV infection in children.
The guidelines are available online at http://www.hivatis.org. Single copies are available by calling ATIS at 1-800-448-0440.
HTML format and PDF format of these guidelines are also available at:
Among HIV-positive patients with moderate-to-severe disease, hyperactivation of CD8+ lymphocytes leads to subsequent CD8+ decline and is highly predictive of disease progression, according to Norwegian investigators. Dr. Dag Kvale of Rikshopitalet in Oslo and associates prospectively monitored 49 HIV-positive patients. "Although CD8+ lymphocytes are believed to be important in the control of HIV infection, few recent studies have examined the prognostic significance of the number of peripheral CD8+ cells," they explain in the February 4th issue of AIDS.
Starting in October 1991, serial serum and plasma samples were obtained for the subjects, who were receiving nucleoside analogue monotherapy or no antiretroviral drug treatment. The observation period was a minimum of 18 months and ended when double or triple combination treatment began or the patient died. At follow-up, 28% of the patients developed AIDS. The results of serial measurements of circulating CD4+ and CD8+ lymphocytes indicated that along with HIV RNA load, the magnitude of CD8+ lymphocyte loss "...was the best independent predictor of AIDS development." The predictive value of CD8+ lymphocyte loss was particularly evident when CD4+ lymphocyte levels were less than 200/µL.
The investigators also found that levels of soluble CD8 antigen, reflecting CD8+ lymphocyte activation, increased in relation to total CD8+ cells in patients who developed AIDS. "Death occurred in 16% of the patients, and was only predicted by high CD8+ cell counts at baseline," they report. They also found that high baseline CD8+ cell counts and HIV RNA were the best predictors of CDC class B or C events, which occurred in 35% of the subjects.
Dr. Kvale's team concludes that "...significant predictive information may be obtained from the serial quantitation of peripheral CD8+ lymphocytes during the progression of HIV infection in patients with moderate to severe immune deficiency [who] are not receiving effective antiretroviral treatment." Their findings also suggest that hyperactivation of CD8+ cells is "...involved in the immunopathogenesis of progressive HIV disease."
Ref: AIDS 1999;13:195-201. Source: CDC HIV/STD/TB Prevention News Update.