Contents
- 12th International AIDS Conference: Guide to tracking abstracts, presentations and reports via the Internet
- Abnormal Fat Distribution and Use of Protease Inhibitors
- Lipodystrophy - An alternative view
- Metabolic Changes: Concerns About Heart, Circulatory Risks
- HIV Mutations Leading to Ritonavir Resistance Identified
- Saquinavir-Resistant HIV Also Highly Resistant to Other Protease Inhibitors
- Long-Lasting Recovery in CD4 T-Cell Function and Viral Load Reduction After HAART
- AIDS-Free Survival Lengthening in Perinatal HIV Infection
- HAART confers significant neuroprotection in HIV-infected patients
PHARMACO INDUSTRY NEWS
- DuPont Pharma, P&U, Glaxo Wellcome, Agouron/Immune Response
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Geneva, 28 th June - 3 rd July 1998 |
Guide to tracking abstracts, presentations and reports via the Internet
The next few issues of AIDS Treatment Projects Doctor Fax will be devoted to coverage of scientific and clinical presentations at the 12 th International AIDS Conference.
Paul Blanchard, Raffi Babakhanian, Simon Collins and other members of ATP will be attending this International meeting which now takes place every 2 years. Raffi Babakhanian is also representing ATP as a delegate at the resistance meeting in Lak e Maggiore this week (we will also be reporting from this important annual event). The 11 th International AIDS Conference from Vancouver in 1996 was, for many, the herald of the modern era of protease inhibitor based combination antiretroviral therapy. The 13 th International AIDS Conference, scheduled for the year 2000, will take place in Durban, South Africa.
Issue 49 of the Doctor Fax is expected to be the first UK publication to carry in depth reports and analysis of conference presentations and is set for distribution on Friday 10 th July.
For those who are unable to attend the conference, but who have access to the Internet, many web sites will carry daily reports, access to abstracts and conference presentation video streams. Below is a selection of those that have come to our attention.
Official Webcast Site
Conference sessions from the 12th World AIDS conference will be available at the official webcast site:
http://webcast.aids98.org/
About 30 to 50 presentations will be av ailable as RealPlayer video streams for review online within eight hours of their initial public viewing in Geneva. In addition, daily summaries of the entire Conference will be available for review and print. The Webcast service will be operational for the duration of the Conference and until 31st December 1999.
The Webcast will be available any time, day or night, and will contain the presenters' voices along with their slides. Each day of the six-day Conference will have up to 50 new presentations together with a summary of daily highlights.
Access to selected posters
The International Association of Physicians in AIDS Care (IAPAC) will be providing an innovative service that will allow Internet access to select posters of cutting edge medical research and late-breaker conference reports presented at the 12th International AIDS Conference within seconds of their presentation. The posters and reports will be posted on the IAPAC Web site: http://www.iapac.org
They will be identical to those presented in Geneva, and will include all graphs, tables, and other relevant illustrations.
On-line summaries
The Clinical Care Options for HIV site will feature comprehensive next-day summaries from the upcoming conference. The summaries, written by leaders in the field of HIV/AIDS, will begin appearing on 30 th June at:
http://www.healthcg.com/hiv/
The summaries will attempt to put the new data in context, integrate the overwhelming amount of new information presented at HIV/AIDS conferences, and offer concise analyses of the clinical implications of the data. They will cover all major clinical presentations and posters at the Conference, including new findings from the areas of epidemiology, pathogenesis, viral markers, antiretroviral therapy, opportunistic infections, women and HIV, paediatrics and HIV, HIV malignancies, and immunotherapies.
Further on-line summaries are also expected to be posted at The Body web site. Check their conference report pages at:
http://www.thebody.com/confs/confcov.html
Other links and reports can also be found at HIV InSite:
http://hivinsite.ucsf.edu
the Johns Hopkins AIDS Service website:
http://hopkins-aids.edu
and The Journal of the American Medical Association HIV/AIDS Information Centre at:
http://www.ama-assn.org/special/hiv/hivhome.htm
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ANTIRETROVIRALS
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Abnormal Fat Distribution and Use of Protease Inhibitors
Several letters to the editor of the Lancet discuss abnormal fat distribution in HIV-positive patients on protease inhibitor therapy. Rebecca Wurtz, of Evanston Hospital , cites two cases of women on protease inhibitor treatment for one year to 16 months who showed new obesity in the abdomen. One woman also had a small buffalo hump and bilateral non-focal supraclavicular fullness, while the other developed substantial proximal muscle wasting in the arms. Neither had hepatosplenomegaly or masses. T. T. Y. Ho and colleagues at the AIDS Unit of the Hong Kong Department of Health observed that seven of 29 patients receiving indinavir for at least three months had noticeable facial wasting. The wasting was characterised by symmetrical loss in the cheeks; the patients failed to show any other abnormal fat distribution. The wasting was not observed in any of the seven patients on other protease inhibitors or in the eight patients who had been taking indinavir for less than three months. Meanwhile, Australian researcher Andrew Carr and colleagues surveyed 148 HIV-infected patients and 47 healthy males for metabolic effects of protease inhibitors. They observed that the central adiposity associated with the drugs was in large part because of peripheral fat wasting lipodystrophy, accompanied by hypertriglyceridaemia, hypercholesterolaemia, and insulin resistance. Type 2 diabetes mellitus was also a rare complication. The fat distribution was not associated with such factors as CD4 lymphocyte count or RNA load, it was not unique to indinavir, the researchers said. They note that many of their patients chose to stop their therapy due to the fat distribution changes, and not due to the risk of vascular disease associated with insulin resistance or hyperlipidaemia. They suggest that "these issues are likely to be of greatest concern in people with early HIV-1 disease for whom protease inhibitor therapy has no proven survival benefit, and are also likely to be increasingly common with long-term therapy."
Ref: The Lancet. Vol 351. 1735-1737. June 6, 1998.
Source: CDC Daily News Update
The journal AIDS also carried a paper by Andrew Carr to which his letter in the Lancet referred:
A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors
Abstract
Objective : To describe a syndrome of peripheral lipodystrophy (fat wasting of the face, limbs and upper trunk), hyperlipidaemia and insulin resistance in patients receiving potent HIV protease inhibitor therapy.
Design : Cross-sectional study.
Setting : Outpatient clinic of a university teaching hospital.
Patients : HIV-infected patients either receiving at least one protease inhibitor (n = 116) or protease inhibitor-naive (n = 32), and healthy men (n = 47).
Interventions and main outcome measures : Lipodystrophy was assessed by physical examination and questionnaire and body composition by dual-energy X-ray absorptiometry. Fasting triglyceride, cholestero l, free fatty acid, glucose, insulin, C-peptide and fructosamine levels, other metabolic parameters, CD4 lymphocyte counts, and HIV RNA load were also assessed.
Results : HIV protease inhibitor-naive patients had similar body composition to healthy men. HIV protease inhibitor therapy was associated with substantially lower total body fat (13.2 versus 18.7 kg in protease inhibitor-naive patients; P = 0.005), and significantly higher total cholesterol and triglyceride levels. Lipodystrophy was observed clinically in 74 (64%) protease inhibitor recipients after a mean 13.9 months and 1 (3%) protease inhibitor-naive patient (P = 0.0001). Fat loss occurred in all regions except the abdomen after a median 10 months. Patients with lipodystrophy experienced a relative weight loss of 0.5 kg per month and had significantly higher triglyceride, cholesterol, insulin and C-peptide levels and were more insulin-resistant than protease inhibitor recipients without lipodystrophy. Patients receiving ritonavir and saquinavir in combination had significantly lower body fat, higher lipids and shorter time to lipodystrophy than patients receiving indinavir. Three (2%) patients developed new or worsening diabetes mellitus.
Conclusion : A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance is a common complication of HIV protease inhibitors. Diabetes mellitus is relatively uncommon.
Ref: Carr A., Samaras K., Burton S., Law M., Freund J., Chisholm D.J., Cooper D.A.: AIDS, 12 (7):F51-F58 (7 th May 1998).
Lipodystrophy - An alternative view
As part of New York's Treatment Action Group's (TAG) monthly meeting Dr. Donald Kotler of St. Luke/Roosevelt's Hospital was invited to share his latest thoughts on the fat redistribution phenomenon showing up in HIV-infected individuals on HAART.
The basis for Kotler's new hypotheses comes from two recently completed studies he has conducted up at St. Luke's (one paper has been submitted to the journal AIDS; the other's three-quarters completed and will be an oral presentation in Geneva). Following his hunch that the "new" reports of strange fat redistribution in people on protease inhibitors were something we've seen since the early days of the epidemic - just not paid much attention to ("When someone comes in with sunken cheeks or a pot belly and sight-threatening or gastric CMV, you tend to focus on the immediately life-threatening condition," he explains.), Kotler went back into his computer database of MRI scans of dozens and dozens of patients from the past year and carefully matched them to MRI scans of HIV-negative controls. What he unearthed was telling: some 40% of patients - none of them on protease inhibitors-exhibited what we now commonly refer to as "truncal obesity." In women, the syndrome manifested itself more often as increased breast size and loss of fat in the upper thighs, but it was there regardless of gender. And, interestingly, it was more evident in people with higher CD4+ T cell counts than in those with lower ones.
In a second, less high-tech study, Kotler used simple callipers and a tape measure to perform anthropometric assessments of patients' waist size and skin thickness. Of some 300 patients, Kotler divided them up into what he called the "old HIV" era (pre-1996) and the "new HIV" era (1996 to the pre sent). (Of the "new HIV" patients, about 50 were taking protease inhibitors, 20 were taking non-protease inhibitor containing antiretroviral regimens and another 20 or so were receiving no therapy at all.) He then matched these to a group of HIV negative controls.
In a multivariate analysis, taking into account treatment or no treatment, protease or no protease, CD4+ cell count, plasma viral load, age, sex, weight and height, the effect of plasma viral load was significantly predictive of the presence of truncal obesity-even after controlling for all other parameters. Use of protease inhibitors and CD4+ T cell count were not. And the correlation was an inverse one: the patients with the lowest plasma HIV RNA levels were the most likely to exhibit truncal obesity!
"What we're seeing is not a loss of fat, but rather a redistribution of fat-away from the peripheral and subcutaneous fat and towards the viscera." Kotler went on to say. "What can, all at the same time, cause hyperlipidaemia, hypercholesterolaemia, h ypertriglyceridaemia, hypertension, hyperglycaemia, lowered testosterone levels, lowered progesterone levels, high uric acid levels and gout?" His hypothesis was announced in the answer. "The answer, in a word: cortisol."
Cortisol, which the body converts from the naturally occurring hormone cortisone, is responsible for the metabolism of glucose, protein and fats. It also regulates the immune system and affects many other bodily functions. Cortisol levels in the body typically display a diurnal patter: elevated in the early morning and then dropping gradually but steadily throughout the day. Cortisol levels are lowest at night. Cortisol and its competitor hormone, adrenaline (a/k/a epinephrine) are produced by the body in response to stress - be it outside stress (such as loud noise or the threat of bodily harm) or internal stress (such as anxiety or disease). Cortisol also causes resistance to insulin, which can lead to a variety of diabetes.
As Kotler tells it, these elevated cortisol levels ("hypercortisolism," if you will) are one of the last remaining legacies of a life threatening condition which has become less life threatening. ("I'm not saying this is hypercortisolism, just that that's certainly what it looks like.") "You see the same thing in women who have survived breast cancer, children who have survived childhood leukaemia. I even had a Vietnam vet who had survived Agent Orange. They all had chronically elevated cortisol levels. They were all people with life threatening illnesses who got better. It's t he body's natural response to stress." "We're just seeing [a big wave of this] in HIV right now because everything's synchronised," Kotler exclaims. "Everybody started AZT at the same time. Then everybody 'failed' at the same time. Now everybody has started protease inhibitors at the same time."
But woe to s/he who would order a simple "fasting serum cortisol" and, upon receiving a reasonable level on the lab print out, proclaims all is well. "The only accurate way to measure cortisol," Kotler cautions, "is a 24-hour urine cortisol." But you have to be willing to collect your urine for a 24-hour period and take it to the lab. (In a study of his own that examined the 24-hour urine cortisol levels of 9 HIV+ patients, 7 of 9 were above normal.)
What of the Sydney (Carr, Cooper et al. AIDS 1998, 12:F51-8, see abstract above) study at last February's retrovirus conference that declared a full 64% ; of protease patients to suffer from various manifestations of "lipodystrophy" you ask? And what of the knee-jerk reaction to categorically link the lipid problem to the protease inhibitors? About the Australian study, Kotler states matter-of-factly that the data were simply "over-interpreted." ("All the patients took protease inhibitors, all the patients' viral load fell dramatically, and they attributed it to the use of protease inhibitors - rather than to the rapid and sustained reduction in plasma virus.")
As for the Falloon study (an NIH study published in the March 21, 1998 issue of The Lancet which unequivocally linked the fat redistr ibution problem to protease inhibitors-indinavir in particular), her team analysed a random sample of patients which included 10 individuals on indinavir who had evidence of truncal obesity, another 10 individuals on indinavir who had no evidence of truncal obesity and 10 controls. "Even though fully half of the patients taking indinavir had no evidence of truncal obesity, the NIH team concluded that the truncal obesity was caused by indinavir!" "It's possible that protease inhibitors are doing something on top of this," Kotler concedes, "but I really don't believe this is anything new." A letter is due to come out soon in The Lancet describing "early onset cardiovascular disease" ( Ref: Henry K, Melroe H, Huebsch J, and others. Severe premature coronary artery disease with protease inhibitors. The Lancet, May 2, 1998; volume 351, page 1328, also ATN article reproduced below ) in individuals living with HIV. With more and more HIV-infected individuals walking around with elevated triglyceride and cholesterol levels, Kotler warns that we're looking at "heart attack city." He thinks a Clinical Alert is warranted. Or a letter to patients:
As the prospects for long-term health have changed, so have the potential complications. If you have noticed any of the following, you should talk to your health care provider:
- a sudden increase in waist size;
- diabetes;
- high total or low HDL cholesterol;
- increased blood pressure.
At the very least, the activist community (or NIH?) should convene a summit of sorts composed of leading HIV physicians. But what the rapeutic interventions exist? Lipid lowering drugs abound (lovastatin, pravastatin, simvastatin, gemfibrozil), and have been met with mixed results. A year or so ago, Kotler recommended steroids and regular exercise. That didn't seem to work. ("So I was wrong," he bats back.) Testosterone supplementation, effective in the non-HIV arena, has also seen little success in HIV. Then there's human growth hormone (at $20,000-30,000 a year). Kotler says he's heard good things about it for the treatment of buffalo hump and truncal obesity but doubts it will help to replace fat lost peripherally (it could also lead to diabetes).
Arguably the most efficient mechanism would be to block the cortisol receptor itself. To date, the most effective agent for this is the controversial French "abortion pill," RU-486. "Maybe you should just eat more fish, less French fries and (as he fingers the Marlboro reds in the pocket of his dungarees) stop smoking."
Author: Mike Barr
Source: TAGline/Volume 5 Issue 5. June 1998
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A special session and other presentations on lipodystrophy are planned for Geneva - watch this space for further developments and reports. |
The following article concerning the Lancet letter on cardiovascular disease and protease inhibitors was published in AIDS Treatment News.
Metabolic Changes: Concerns About Heart, Circulatory Risks
A May 2 research letter in The Lancet, by AIDS, lipid, and cardiology specialists at Regions Hospital in St. Paul and the University of Minnesota Medical School in Minneapolis, highlighted growing concerns that high cholesterol and other metabolic changes being seen in some HIV patients may be increasing the risk of heart and circulatory disease. (1) The letter was prompted by two cases of unusual coronary artery disease in young men being treated with protease inhibitors; there has since been a third case. These incidents led to a chart review of 124 patients on protease inhibitors, which found that 33% of them had high enough lipid (fat) concentrations in their plasma to be referred for treatment, either with diet and exercise or with lipid-lowering drugs.
The Regions Hospital HIV clinic has developed interim recommendations, including getting baseline blood tests before starting protease inhibitors, lifestyle changes such as improved diet and stopping smoking, and treatment when necessary according to the U.S. National Cholesterol Education Program (NCEP) guide lines for lowering cholesterol in patients with heart disease. (2)
In a phone conversation on May 11, lead author Keith Henry, M.D., explained why this problem may be more important than some have realised:
- Cardiovascular disease usually develops over decades; this is why heart attacks usually happen to people who are older. If this process is accelerated in some HIV patients - either because of the virus, or because of some of the drugs used to treat it - damage could be happening now, which could show up increasingly over the next few years. The Regions Hospital HIV Clinic has not had any deaths from heart problems yet, but Dr. Henry has heard of cases from other physicians.
- High cholesterol levels may be a bigger problem than widely realised, since in many of these patients the triglycerides are also high, which can prevent the cholesterol from being measured accurately. The abnormal fat which may be contributing to cosmetic changes in some patients is carried through the circulation, with unknown effects on parts of the body which are not seen. And a modest total cholesterol elevation can be worse than it looks, because it often consists of a combination of an increase in LDL cholesterol (the "bad" cholesterol) and a decrease in the HDL cholesterol (the "good " cholesterol).
- Lifestyle problems, including smoking, poor diet, and lack of exercise, are likely to increase the risk further. Many patients are not on good diets, since in the past the goal has been just getting calories in.
- There are interim measures th at can be taken now. The Regions Hospital clinic obtains a fasting lipid profile before starting patients on protease inhibitors, and then 3-6 months after. Abnormalities are treated according to the NCEP guidelines--just as the same conditions would be t reated in HIV-negative persons with heart disease.
Source: AIDS TREATMENT NEWS Issue #295, May 15, 1998. Subscription and Editorial Office: P.O. Box 411256 San Francisco, CA 94141
References
- . Henry K, Melroe H, Huebsch J, and others. Severe premature coronary artery disease with protease inhibitors. THE LANCET May 2, 1998; volume 351, page 1328.
- . National Institutes of Health. CHOLESTEROL LOWERING IN THE PATIENT WITH CORONARY ARTERY DISEASE: Physician Monograph--National Cholesterol Education Program. September 1997 (NIH Publication 97-3794). This document is available at: http://www.nhlbi.nih.gov/nhlbi/cardio/chol/prof/chol_low.htm
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The utility of lipid lowering drugs , lifestyle and dietary interventions are, as yet, of uncertain efficacy in this setting. Whether the end result of chronic disease or an adverse effect on protease inhibitor therapy, we need data and guidance, and quickly, on the best way to manage this complication of HIV-disease. |
HIV Mutations Leading to Ritonavir Resistance Identified
Dr. P. Scott Eastman of Chiron Corp. an d colleagues report in the June issue of the Journal of Virology that they have classified an ordered accumulation of mutations in HIV that lead to resistance of ritonavir. The researchers studied 10 HIV-infected patients who were receiving protease inhibitor treatment with ritonavir and detected three mutation types that lead to the emergence of ritonavir resistance. The researchers identified V82A/F as a primary mutation and I54V as a secondary mutation, with secondary rebounds in HIV RNA levels associated with I54V-V82A double mutations. A high prevalence of the L63P/A mutation was detected in subjects prior to treatment; the mutation may be active in stabilising the V82A/F mutation. The researchers also note that "...no patient with plasma levels [greater than] 2000 copies/mL at the nadir experienced a virologic benefit greater than 60 days." This is consistent with estimates for the conversion of the viral population to a single mutant genotype, based on the V82A-type doubling time of 2.4 to 4.8 days .
Source: CDC Daily News Update
Ref: J Virol 1998;72:5154-5164.
Saquinavir-Resistant HIV Also Highly Resistant to Other Protease Inhibitors
Viral mutations selected by the HIV protease inhibitor saquinavir confer high levels of cross-resistance to other protease inhibitors. Dr. Mark A. Winters and others from the Center for AIDS Research at Stanford, California, report the finding in the June issue of the Journal of Virology.
The researchers sequenced the HIV protease gene from 16 patients who had failed to maintain viral load suppression on saquinavir therapy and subsequently switched to nelfinavir or indinavir. Patients had received either 3,600 or 7,200 mg/day of saquinavir, and had an average overall saquinavir exposure of 77 weeks, with or without reverse transcriptase inhibitors.
The group reports that the G48V mutation in HIV protease developed significantly more often in these patients than in previously studied patients who received saquinavir 1,800 mg/day for a mean of 46 weeks. There was also an increase in the frequency of the V82A mutation.
When viral isolates were evaluated for sensitivity to protease inhibitors, seven isolates from five patients were found to have reduced susceptibility to saquinavir, nelfinavir and indinavir. Isolates from six patients were less susceptible to saquinavir and nelfinavir, but retained sensitivity to indinavir.
"With one exception, reduced susceptibilities to nelfinavir were found in all isolates having reduced susceptibilities to saquinavir, including patients who were treated only with saquinavir," the authors write.
All patients who developed the G48V mutation also developed the V82A mutation either on saquinavir therapy or after switching to nelfinavir or indinavir. The authors suggest that "...the G48V-V82A genotypes that developed during saquinavir therapy were expanded and potentiated during subsequent therapy with either nelfinavir or indinavir."
Dr. Winters' team also notes that in vitro susceptibility assays showed that "...all 13 isolates with reduced susceptibilities to two or more protease inhibitors had either the G48V or L90M mutation, along with an average of six other protease mutations."
The authors conclude, "Mutations selected in vivo by initial saquinavir therapy may provide more cross-resistance to the other protease inhibitors than has been previously reported." They add that their results support the hypothesis that "...initial therapy with one protease inhibitor may compromise the usefulness of subsequent protease inhibitors."
Ref: J Virol 1998;72:5303-5306.
Source: CDC Daily News Update
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Does increased evolutionary pressure with high dose HGC (or SGC) give a more obvious pattern of resistance and cross-resistance? As predicted, cross-resistance amongst the currently licensed group of PI's (all peptomimetic) is widespread and not predictable by initial mutation site. |
Long-Lasting Recovery in CD4 T-Cell Function and Viral Load Reduction After Highly Active Antiretroviral Therapy in Advanced HIV-1 Disease
French researchers report the sustained recovery of CD4 T-cell reactivity against opportunistic pathogens in patients with advanced HIV disease following highly active antiretroviral therapy (HAART). T. S. Li and colleagues of the Hospital Pitie-Salpetiere in Paris, France, followed 20 patients - seven naive and 13 who had previously received antiretroviral therapy - for one year, checking CD4 cell proliferation and response to tuberculin and cytomegalovirus antigens at months one, three, six, nine, and 12. Four of the patients had antigen-specific reactions at baseline, versus 14 after one year. Ten patients were considered responders - six of the naive and four of the previously treated - showing viral load reductions sustained for 12 months. The responders also exhibited an early rise in memory CD4 T-cells and naive T-cells, as compared to non-responders. The authors found that the recovery depends on the amplitude and duration of viral-load reduction and the increase in memory CD4 T-cells, not baseline levels.
Ref: Lancet (06/06/98) Vol. 351, No. 9117, P. 1682; Li, T. S.; Tubiana. R.; Katlama, C.; et al.
Source: CDC Daily News Update
AIDS-Free Survival Lengthening in Perinatal HIV Infection
Dr. Vadim Pliner of the Medical and Health Research Association of New York City, Inc., and colleagues found that 48 percent of 190 children perinatally infected with HIV-1 between 1986 and 1997 developed AIDS by age three, with AIDS progression falling to 3 percent annually after that time. The researchers, part of the multicentre New York Perinatal Transmission Collaborative Study Group, calculated that one-third of the children would still be AIDS-free at age 13. Disease progression was as sociated with the year of birth, with the time to progression increasing over the years.
Source: CDC Daily News Update
HAART confers significant neuroprotection in HIV-infected patients
Highly active antiretroviral treatment (HAART) is more likely than less potent regimens to protect neuropsychological function in HIV-infected patients, according to research conducted at Cornell University Medical College in New York.
As part of a longitudinal study of psychosocial adjustment to AIDS, Dr. Stephen Ferrando and colleagues administered a battery of neuropsychological tests to 130 men, average age 41 years, who were HIV-positive or had AIDS. Forty-two percent of the patients were non-white.
Dr. Ferrando's team classified a patient as receiving HAART if he had been "...taking two or more [nucleoside analogue reverse transcriptase inhibitors] with or without nevirapine or delavirdine with ritonavir, indinavir or nelfinavir for 1 month or more," according to their report in the May 28th issue of AIDS. By this definition, 53% of the patients were taking HAART and 47% were taking less potent antiretroviral regimens.
The researchers detected neuropsychological impairment in 22% of the HAART group and 45% of the other patients. The HAART group performed significantly better than the other patients on tests of "...attention, concentration, learning, memory and psychomotor speed."
In some patients the neuroprotective effects of HAART were evident as early as 1 to 6 months after the initiation of therapy, the investigators found.
Patients who were neuropsychologically impaired were more likely than unimpaired patients to be non-white, to have no post-high school education, and to use sedatives. Even after the data were adjusted to account for these factors, HAART was a significant predictor of neuropsychological status.
CD4 cell counts in patients taking HAART were significantly lower than in those not taking HAART, but the viral load in patients taking HAART was more likely to be undetectable. Dr. Ferrando's group concludes, "...HAART benefits neuropsychological function through the reduction of viral load."
Ref: AIDS 1998;12:F65-F70.
Source: CDC Daily News Update
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PHARMACO INDUSTRY NEWS
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DuPont Merck Submits New Drug Application for efavirenz (Sustiva TM)
The DuPont Merck Pharmaceutical Company has announced its submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for its investigational, once-daily anti-HIV drug efavirenz (formerly known as DMP-266). The company is seekin g accelerated approval of efavirenz based on data collected during numerous trials involving more than 2,000 HIV-infected individuals. Efavirenz is a member of the non-nucleoside reverse transcriptase inhibitor (NNRTI) class of antiretrovirals.
Efavirenz is generally well tolerated; side effects include rash, nausea, dizziness, diarrhoea, headache and insomnia. Severe rashes have been reported in less than one percent of patients. Pregnant women should not take this new medication unless the potential benefit to the mother outweighs the potential risk to the foetus.
The marketing applications for Sustiva will also be submitted to European and Canadian regulatory authorities.
Upjohn to Sell Out?
Rumours, partially confirmed by company officials, indicate that Pharmacia & Upjohn is considering selling its HIV drugs or at least finding a partner for their further development. The product line includes first of all the FDA-approved NNRTI delavirdine (Rescriptor). Sales of delavirdine, which went on the market in the U.S. a year ago, have been disappointing. Delavirdine has suffered in the market mostly because of the lack of trial data demonstrating a solid anti-HIV effect and an inconvenient dosing schedule consisting of four tablets three times a day. Its skin rash problems are less serious than those of the competing NNRTI nevirapine, however.
Upjohn has continued to research the drug, especially after a trial of AZT/3TC/delavirdine in a treatment-naïve cohort did find HIV suppression comparable at least to nevirapine, if not efavirenz. Ongoing delavirdine trials test various three and four drug delavirdine containing regimens, a paediatric formulation, and delavirdine's contribution to salvage therapy regimens.
Upjohn is also developing an NNRTI designed to be effective against delavirdine resistant HIV, but this delavirdine backup agent has not yet undergone human testing.
P&U's most intriguing anti-HIV drug right now is its experimental protease inhibitor, which because of its unique structure, should have activity agains t HIV resistant to the currently available protease inhibitors. Initial dose-escalation studies of this compound, designated PNU140,690, have been completed and a dose of 1,500 mg three times a day selected for further study. This dose requires taking a t otal of 30 tablets. Upjohn is developing a 300 mg pill in an attempt to reduce the pill burden - if patients can swallow tablets that large - and is also exploring formulations that increase the drug's absorption by the intestines.
A salvage therapy trial is about to commence, too, covering individuals with viral loads over 5,000 after taking indinavir or ritonavir plus two other anti-HIV medications for at least six months. Volunteers will replace their previous protease inhibitor with PNU140,690 for four weeks before being allowed to switch the other two drugs too. This approach, which is virtual monotherapy, may favour the development of drug resistance. P&U will have to show that it believes in this drug to get volunteers to swallow a risk like that along with all the tablets. Putting it up for sale is not a sign of faith, though.
Author: Dave Gilden
Source: Treatment Issues, Volume 12, Number 5 - May 1998
Glaxo Buys in
While Upjohn moves to reduce its presence in the HIV arena, Glaxo just gets in deeper . The company already has two new antiretrovirals, abacavir and amprenavir, that may reach the market by the end of this year. In addition, it recently bought a family of structurally related NNRTIs from Hoechst Marion Roussel to complete its anti-HIV pro ductrange.
The original lead NNRTI was HBY 097, which has already been tested in a small number of humans and looked very good in its initial run-through. Viral load drops of greater than one log (90%) after 14 days of monotherapy were observed, without the appearance of drug-resistance mutations in participants' HIV. During a 1996 interview with Treatment Issues, famed HIV drug discoverer Eric DeClercq said of HBY 097, "It's... within the top few compounds that we have analysed ourselves. I hope it will b e developed."
But development of HBY 097 was in fact terminated. The compound's short half-life in the body and large required dose led to an onerous dosing schedule and concerns about possible toxicity's and interactions with other drugs. Glaxo is now starting back at the beginning with the compounds, evaluating candidate NNRTIs for anti-HIV activity and drug-resistance profiles.
Author: Dave Gilden
Source: Treatment Issues, Volume 12, Number 5 - May 1998
Agouron to exclusively market Remune HIV therapy
Agouron Pharmaceuticals, based in La Jolla, California, licensed exclusive marketing rights in North America, Europe and certain other countries to Immune Response's HIV treatment, Remune.
Remune is an immune-based therapy developed by Immune Response and is currently in phase III studies. The companies agreed to collaborate on the final development and commercialisation of the drug. They expect to file for approval next year, according to a joint company press release posted on PR Newswire.
Agouron has certain rights to terminate the deal, which calls for Immune Response to receive as much as $77 million during the next 2 years. The compensation includes licensing and milestone payments of $45 million, development support of $18 million, and the purchase of $14 million of Immune Response's stock by Agouron.
Initially, Carlsbad, California-based Immune Response will receive a $10 million license fee. As part of the transaction, Agouron has already purchased 118,256 shares of Immune Response common stock for $ 2 million. The companies will share profits equally once the drug is commercialised.
Agouron currently markets the HIV protease inhibitor nelfinavir mesylate (Viracept). Agouron said that it would sponsor a new trial of Remune in combination with highly active drug regimens that contain Viracept.
The current phase III study of Remune includes 2,500 patients at 74 centres in the US. The companies expect the trial to conclude in April 1999. In addition, more than 300 patients are enrolled in two other studi es to evaluate the effect of Remune in combination with antiretroviral drugs, and a smaller study at the National Institutes of Health is being conducted on children infected with HIV.
Peter Johnson, president and CEO of Agouron, said in the statement, "We made the decision to aggressively pursue this opportunity with Immune Response after a comprehensive review of clinical data of Remune from a number of studies, which convinced us of the unique potential of this product to make a powerful contribution t o the treatment of HIV infection and AIDS."
He added, "Prominent among these data were encouraging preliminary results from a study of Remune taken in combination with highly active antiretroviral drugs results that will be presented at the upcoming 12th W orld AIDS Conference in Geneva later this month."
Source: CDC Daily News Update
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REMUNE is an immune-based therapy composed of inactivated HIV, depleted of its outer coat (gp120) and emulsified in Incomplete Freund's Adjuvant. The treatment regimen is very easy for a patient to follow as it requires one injection every three months. Adverse reactions have generally been limited to pain and/or swelling at the site of injection which subsides in one to two days. REMUNE can be used alone or in conjunction with antiviral drugs. |