Medical Consultant
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6th Conference on Retroviruses and Opportunistic InfectionsJanuary 31 - February 4, 1999 - Chicago, IL
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ATP DR FAX Symposium III
Optimising First-Line and Salvage Therapy:
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ANTIRETROVIRALS
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Efavirenz effective in non-zidovudine containing regimens
Paul Blanchard, ATP
Data were presented at the 9th European Conference of Clinical Microbiology and Infectious Diseases, Berlin March 21-24 from study DMP 266 - 043 on the combination of efavirenz (EFV) administered with stavudine (d4T) and lamivudine (3TC). This study is an open label, single arm, multicentre trial of 48 week duration. 24 week data on the first 42 patients enrolled was presented; patients were naive to all antiretroviral therapy on enrolment. Efavirenz was administered at 600mg, once daily in combination with d4T 30-40 mg twice daily and 3TC 150 mg twice daily.
The 42 patients out to 24 weeks had baseline mean viral load of 75,858 copies/ ml and mean CD4 counts of 380 cells/mm3. Using an intent to treat non-completer equals failure analysis (ITT, NC=F), after 24 weeks of treatment, 92% of patients achieved viral loads BQL (< 400 copies/ml) and 89% achieved viral loads of <50 copies/mL. A mean increase in CD4 cells of 169 cells/mm3 was also observed. There were no discontinuations due to adverse events.
Efficacy of this combination did not appear to be affected by higher baseline viral load with 11/12 patients with starting viral loads greater than 100,000 copies/mL also achieving <50 copies/mL at 24 weeks.
Ref: C. Cohen, R. Elion, S. Green, M. E. Eyster, D. F. Labriola, D. J. Manion, S. L. Boyko, N. M. Ruiz and the Study 043 Team. A Phase II, Open- Label, Multicenter Study to Characterize the Effectiveness and Safety of Efavirenz (EFV) in Combination with Stavudine (d4T) and Lamivudine (3TC) in Antiretroviral- Naďve HIV- Infected Patients (Study DPC 266- 043). 9th ECCMID, European Congress of Clinical Microbiology and Infectious Diseases, 21st-24th March, 1999. Berlin.
Abacavir plus an NNRTI may be an effective salvage regimen for patients failing PI based therapy
Paul Blanchard, ATP
A retrospective analysis of patients in the UK abacavir (ABC) expanded access programme was performed to identify the responses of those who also received a non-nucleoside reverse transcriptase inhibitor (NNRTI). All identified subjects were NNRTI naďve but protease inhibitor experienced and received ABC along with open-label efavirenz (EFV) or nevirapine (NVP). Background therapy was also allowed with 81% of subjects on 2 further antiretrovirals, 6% on 3 additional drugs, and 3% (1 subject) on 4 additional drugs.
A total of 31 subjects were identified, 18 of whom received efavirenz the other 13 receiving nevirapine. All subjects had received extensive prior treatment with a wide range of antiretrovirals excluding abacavir or NNRTI's. Mean viral load was high at approximately 283,707 copies/mL (5.45 log).
Results presented changes from baseline as below:
| Results | Week 8 | Week 16 | Week 24 | |
| VL | EFV | -1.98*
(n=17) | -1.95*
(n=14) | -1.98*
(n=12) |
| NVP | -0.92*
(n=13) | -0.57
(n=8) | -0.87*
(n=9) | |
| CD4 | EFV | +75.7*
(n=15) | +71.3*
(n=14) | +97.4*
(n=12) |
| NVP | +22.6
(n=11) | +25.2
(n=10) | +25.7
(n=9) |
*=p(0.05
Five deaths secondary to HIV progression were seen, four in the NVP group and one in the EFV group.
These results suggest that the combination of abacavir with an NNRTI in this group of advanced patients shows some virological and immunological benefit. Efavirenz appears to perform better in these patients than nevirapine, although it should be noted that the nevirapine group had a lower mean starting CD4 count (36 cells/mm3, range 0-110) when compared to the efavirenz receiving patients (57 cells/mm3, range 2-264)
Ref: Moyle GJ, Wilkins E, Leen C, Reynolds B, Gazzard BG. Salvage therapy with abacavir (ABC) plus efavirenz (EFV) or nevirapine (NVP) in HIV-1 infected persons with CD4 count <100/mm3 and prior protease inhibitor (PI) therapy. [Abstract O27]. Fifth Annual meeting of the British HIV Association, Churchill College, Cambridge, March 26-28 1999.
Sexual dysfunction associated with protease inhibitor (PI) use
Joan Tallada, GTT, Barcelona.
A letter in the March 6th issue of The Lancet from a Spanish hospital reports on sexual dysfunction (SD) in men likely associated to PI use. Dr Eduardo Martínez and colleagues, from Hospital de Galdakao, in Vizcaya (Northern Spain), have monitored 14 young HIV-infected men (mean age 37.4 years, average CD4+ count 374 cells/mm3, each patient with a viral load of less than 200 copies/ml) who complained of sexual dysfunction. The symptoms reported included erectile dysfunction and, less commonly, ejaculatory inability and loss of libido. None of the patients had suffered these symptoms in the past, even when they were in poorer health or while receiving previous NRTI-only drug combinations.
Most individuals had HCV co-infection, although none showed clinical or biochemical evidence of liver insufficiency. At the time of occurrence of SD all subjects were on combination therapy including NRTI plus PI for a mean period of 9.4 months (range 2-20).
With the exception of drug use, none of the organic causes of male impotence were present. The authors considered that ketoconazole use in some patients to improve saquinavir plasma concentrations was not directly related to SD due to the lower-than-standard ketoconazole dose prescribed and the lack of low testosterone concentrations. Other minor changes of endocrinological substances detected were also unlikely to be correlated with impotence. Also, AIDS related SD was not pertinent in these 14 men, as all of them were in good health at the time they developed symptoms.
The authors finished their letter by stating that "...taking into account that we care for about 260 HIV infected men treated with PI, the occurrence of such a large number of cases in 14 months represents a high incidence compared with that expected in the general population of the same age group. It is remarkable that sexual dysfunction has not been reported to date, despite the widespread use of protease inhibitors".
Ref: Eduardo Martínez, Julio Collazos, José Mayo, María Soledad Blanco. Hospital de Galdakao, Vizcaya (Spain). Sexual dysfunction with protease inhibitors. Letter to The Lancet, vol 353, March 6, 1999, page 810.
Effects of HIV-1 resistance to protease inhibitors on reverse transcriptase processing, activity, and drug sensitivity
Abstract
Human immunodeficiency virus type 1 (HIV-1) variants resistant to protease inhibitors often display a reduced replicative capacity as a result of an impairment of protease function. Such fitness-impaired viruses display Gag precursor maturation defects. Here, we report that some protease inhibitor-resistant viruses also display abnormalities in the processing of reverse transcriptase (RT) by the protease. In three recombinant viruses carrying resistant protease sequences from patient plasma, we observed a marked decrease in the amount of mature RT subunits and of particle-associated RT activity compared to their parental pretherapy counterparts. We investigated the possibility that a decrease in the amount of particle-associated mature RT could affect the sensitivity of the corresponding virus to RT inhibitors. We observed a twofold increase of sensitivity to zidovudine (ZDV) when a virus which carried ZDV mutations was processed by a resistant protease. Interestingly, the presence of ZDV-resistance mutations partially rescued the replication defect associated with the mutated protease. The interplay between resistance to protease inhibitors and to RT inhibitors described here may be relevant to the therapeutic control of HIV-1 infection.
Ref: de la Carriere LC, Paulous S, Clavel F, Mammano F. J Virol 1999 Apr;73(4):3455-9
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OBSTETRICS
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With about 2.3 million HIV-infected women world-wide giving birth each year, mother-to-child transmission of the virus raises serious public health concerns. Scientists believe that about 70
percent of vertical transmission cases occur during labour and delivery. The AIDS Clinical Trial Group 076 previously determined that administration of zidovudine could significantly reduce the rate of vertical transmission. A recent meta-analysis of 15 studies by the International Perinatal HIV Group published in the New England Journal of Medicine (see below) showed that elective caesarean section delivery can help reduce the vertical transmission of HIV. The authors, though, point out that HIV-positive pregnant women must decide if the benefits of such surgery outweigh the risks of the procedure, which can be significant in immunocompromised women. In an editorial, Drs. Laura E. Riley and Michael F. Greene of Massachusetts General Hospital note that it is unlikely other studies on the subject will be conducted. "The use of highly active antiretroviral therapy alone will probably reduce the rates of vertical transmission so much that studies to demonstrate a further reduction in risk with caesarean delivery would need to be impossibly large," assert Riley and Greene. They add that caesarean delivery may not be useful for women with very low viral loads and for women who are at risk of complications due to high viral loads and low CD4+ cell counts. However, they believe that the procedure may be beneficial in areas where highly active antiretroviral therapy is not widely available.
Ref: Riley, Laura E.; Green, Michael F. New England Journal of Medicine (04/01/99) Vol. 340, No. 13, P. 1032.
Source: CDC HIV/STD/TB Prevention News Update
The mode of delivery and the risk of vertical transmission of HIV-1
The International Perinatal HIV Group conducted a meta-analysis of 15 prospective cohort studies to determine the association between caesarean section and vertical HIV-1 transmission. Analysing data from 8,533 mother-child pairs, the researchers said "this meta-analysis suggests that elective caesarean section reduces the risk of transmission of HIV-1 from mother to child independently of the effects of treatment with zidovudine." They report that the elective surgery resulted in a reduction of transmission measuring about 50 percent, after adjusting for antiretroviral therapy, maternal stage of disease, and infant birth weight. The combination of antiretroviral therapy and elective caesarean section resulted in an 87 percent reduction of HIV-1 transmission risk. Among mothers who received antiretroviral therapy, those undergoing caesarean section had a 2 percent rate of mother-to-child HIV-1 transmission, while those utilising other modes of delivery had a 7.3 percent rate of vertical transmission.
Ref: New England Journal of Medicine (01/04/99) Vol. 340, No. 13, P. 977
Source: CDC HIV/STD/TB Prevention News Update
Elective caesarean-section versus vaginal delivery in prevention of vertical HIV-1 transmission: a randomised clinical trial
The European Mode of Delivery Collaboration conducted randomised clinical trials to assess possible vertical HIV transmission risk-reduction associated with caesarean-section delivery. The researchers assigned eligible HIV-positive pregnant women for either elective caesarean delivery or for vaginal delivery. Of 370 infants born to the women, 170 infants were born to women assigned to the elective caesarean- section delivery group. Three of these children (1.8 percent) were found to be HIV-positive by age 18 months. Comparatively, 21 of the 200 children (10.5 percent) born to women designated for vaginal delivery were HIV-positive after 18 months. Seven of 203 infants (3.4 percent) who were actually delivered through caesarean section contracted HIV, while 15 of 167 (10.2 percent) of children delivered vaginally contracted the virus. The researchers conclude that "elective caesarean-section delivery significantly lowers the risk of mother-to-child transmission of HIV-1." They add that few postpartum complications and no serious side effects were observed among any of the women.
Ref: Lancet (27/03/99) Vol. 353, No. 9158, P. 1035
Source: CDC HIV/STD/TB Prevention News Update
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It should be emphasised that both reports are of the added value of caesarean section in the setting of either no antiretrovirals or zidovudine monotherapy only - this is no longer a standard of care. As the accompanying NEJM editorial states "...since that time, newer antiretroviral agents and combination antiretroviral therapy have entered obstetrical practice. Clinicians are aware that highly active antiretroviral therapy significantly decreases maternal viral load (often to nondetectable levels), and this approach should lower the risk of vertical transmission regardless of the mode of delivery. Thus, the question now is whether elective cesarean delivery will still be protective with the use of highly active antiretroviral therapy."
In an accompanying commentary to the Lancet paper (Lancet (27/03/99) Vol. 353, No. 9158, P. 1030) C N Hudson of St. Bartholomew's Hospital in London, notes that "the need to explain to others why she [the mother-to-be] is having an elective caesarean section for which there is no obvious reason may be a strong disincentive, especially if the woman's HIV-1 status is not known to her partner." The author asserts that the surgery, when used, should be part of a transmission-reduction package that includes breast feeding avoidance and antiretroviral therapy. |
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IN BRIEF
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Dutch researchers report that each year, about one-quarter of patients who receive highly active antiretroviral therapy (HAART) discontinue their initial regimen. A study published in the March 1 issue of the Journal of Acquired Immune Deficiency and Human Retrovirology showed that of 99 patients followed for 450 days, three patients withdrew from treatment and 27 patients altered their HAART regimen. Additionally, more than 50 percent of patients with low CD4+ cell counts discontinued initial treatment within one year. The authors concluded that many patients discontinue initial HAART treatment because of insufficient response to treatment or due to side effects.
Ref: J Acquir Immune Defic Syndr Hum Retrovirol 1999; 20:290-294.
Source: CDC HIV/STD/TB Prevention News Update
Ritonavir and excessive menstrual bleeding
Sean Hosein, CATIE
Protease inhibitors are associated with several side effects. Dr. Henrik Nielson in Denmark has reported excessive menstrual bleeding in four of 10 women treated with ritonavir (with or without saquinavir). None of these women had experienced heavy bleeding before HAART, yet within two months of starting a ritonavir regimen, all four women developed an unusual level of bleeding. One woman even required a transfusion because of severe anaemia. Three of the four were switched to another protease inhibitor without any further complications. The remaining woman continued to use ritonavir, although her periods are somewhat irregular.
Exactly why this happened is not certain, since HIV-infection itself does not appear to increase bleeding during periods. Indeed, none of the women reported unusual menstrual problems before the start of HAART. Other questions to consider are whether similar problems will occur with the use of other protease inhibitors or whether this problem only occurs shortly after HAART is began. Further research is clearly needed. Nevertheless, HIV-infected women and their care providers may need to be aware of this potential complication.
Ref: Nielson H. Hypermenorrhoea associated with ritonavir. Lancet 1999;353:811-812.
Source: TreatmentUpdate 96 - 1999 March, Volume 11 Issue 2. From Community AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca
Rate of false negative results for Pap smears higher in HIV-infected women
According to a report presented at a meeting of the Society of Gynecologic Oncologists held earlier this week in San Francisco, Pap smears performed on HIV-positive women are more likely to give false negative results than those performed on HIV-negative women.
Dr. Annekathryn Goodman of the Massachusetts General Hospital reported the results of a study of 184 women at high risk for HIV infection. Eighty-two of the women were HIV negative and 102 HIV positive. In addition to Pap smears, the women were subjected to blood tests, colposcopic exams and biopsies of the cervix. The research team discovered a significantly higher rate of false negative Pap test results among the HIV-positive women. Specifically, their analysis revealed a false negative rate of 37% among HIV-positive subjects compared to 21.4% in HIV-negative subjects.
In addition to annual or semi-annual Pap tests, Dr. Goodman urged that HIV-positive women with additional risk factors for cervical cancer, such as multiple sexual partners or injection drug use, undergo yearly colposcopic examinations. This form of screening allows a doctor to view an enlarged image of the cervix through the use of an optical device complete with light and magnifying lens.
Source: CATIE-News, From Community AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca
Nevirapine may be effective against vertical HIV-1 transmission
Research conducted by Dr. Philippa Musoke of the Makerere University in Kampala, Uganda, and others indicates that a single dose of nevirapine administered to HIV-1-infected women during labour and to their infants during the first week of life is safe and well tolerated by the patients. The researchers believe that the drug may be helpful in reducing the transmission of HIV-1 from mother-to-child. Twenty-one HIV-1-positive Ugandan women and 13 of their infants were given the drug and monitored for six weeks; there were no serious side effects and the drug stayed in the mothers' and infants' plasma for a prolonged period. The authors, who report their findings in the March 11 issue of AIDS, said that the antiviral activity of the drug appeared to be potent, resulting in a decrease in maternal HIV-1 RNA levels.
Ref: AIDS 1999;13:479-486.
Source: CDC HIV/STD/TB Prevention News Update
Low cardiorespiratory fitness in HIV-infected teenagers
Dr. Ligia Peralta and colleagues at the University of Maryland in Baltimore report that many HIV-infected teenagers have poor cardiorespiratory capacity. Dr. Peralta and colleagues studied three male and six female HIV-infected adolescents taking double- or triple-antiretroviral therapy to determine if cardiorespiratory insufficiency was the cause of their excessive fatigue. The Baltimore team matched the subjects with HIV-negative counterparts and continuously measured oxygen uptake and heart rate during maximal treadmill exercise testing in both groups.
At the annual meeting of the Society of Adolescent Medicine in Los Angeles, Dr. Peralta reported that the HIV-infected group had a mean peak heart rate of 157 beats per minute compared with a peak heart rate of 200 to 220 beats per minute in controls. The mean peak oxygen uptake level in the HIV-infected adolescents was 22.7 mL/kg per minute compared with 38.7 mL/kg per minute in the control group.
The researchers found that the HIV-positive teenagers in this study reported low levels of vigour but did not realise that their fatigue was caused by their medical condition, Dr. Peralta noted. Fatigue in HIV-infected adolescents "...is underestimated, underreported, and mistreated," she asserted. "Physicians need to know this problem exists and can be improved by [aerobic] conditioning."
Source: CDC HIV/STD/TB Prevention News Update
Time to AIDS not altered by injection drug use
A multicentre team reports that injection drug use has only a "negligible effect" on the progression of HIV disease. Therefore, they conclude that the same guidelines developed to treat other HIV-infected patients should be used to treat this subgroup. Dr. Patrizio Pezzotti of the Istituto Superiore di Sanita in Rome and colleagues examined the data from two prospective cohorts of HIV-infected patients. Information on a total of 1,003 injection drug users (IDUs) from either the AIDS Link to Intravenous Experiences (ALIVE) group or the Italian Seroconversion Study (ISS) was examined. Subjects in the ALIVE group were primarily polydrug injectors, while subjects in the ISS were mostly opiate injectors.
Dr. Pezzotti's team estimated the rate of disease progression in these subjects, while adjusting for sex, year of seroconversion, and age at seroconversion. The results of "...multivariate analyses that adjusted for age showed no significant differences by cohort, gender, race, or time of seroconversion." Specifically, they found that for 25-year-olds, the median time to AIDS in the ALIVE cohort was 12.3 years and the median time to AIDS in the ISS cohort was 11.8 years. In the 35-year-olds in both groups, the median time to AIDS was a little more than 8 years. "These estimates were similar to those for non-IDUs observed in the ISS and to those from [a] large cohort of homosexual men," they add. Overall, the data indicate "...a negligible effect of injection drug use on HIV progression."
Ref: J Acquir Immune Defic Syndr Hum Retrovirol 1999;20:275-282.
Source: CDC HIV/STD/TB Prevention News Update
T cell activation most important survival predictor in advanced HIV-1 infection
Among patients with advanced HIV-1 infection, T lymphocyte activation is more closely associated with shorter survival than are viral load or chemokine coreceptor usage, according to a multicentre team.
"Only a few studies have addressed determinants of survival in advanced HIV-1 disease," Dr. Janis V. Giorgi of the UCLA School of Medicine and associates explain. The researchers therefore investigated immunologic and virologic parameters associated with survival in 37 HIV-1-infected patients with CD4+ cell counts of 50/µL or less. The investigators used specimens from members of the Multicenter AIDS Cohort Study that were collected before HAART was available.
They found that severe CD4+ T cell immunodeficiency correlated with high viral load, low levels of naive T cells, and T cell activation as determined by expression of CD38. However, "...T cell activation plays a predominant role in determining survival in advanced HIV-1 infection," they report in the April issue of the Journal of Infectious Diseases.
Specifically, Dr. Giorgi's group found that "...shorter survival was associated with elevated cell surface expression of CD38 activation antigen on CD4+ and CD8+ T cells, elevated Fas expression on CD8+ cells, and an increased percentage of CD45RO+CD38+CD8+ T cells."
Conversely, they observed that neither plasma viral load nor viral chemokine coreceptor usage (CCR5 or CXCR4 or both) correlated with length of survival.
Based on the findings, Dr. Giorgi's group concludes that "...even though other variables certainly contribute to differences in rate of disease progression during the prolonged course of chronic HIV-1 infection, once the advanced stage of disease is reached, T cell immune activation is the predominate determinant of differences in survival time."
Ref: J Infect Dis 1999;179:859-870.
Source: CDC HIV/STD/TB Prevention News Update
New antiviral substances found with HCG
John S. James, AIDS Treatment News
HCG (human chorionic gonadotropin) is an approved drug which is prepared from the urine of pregnant women. Some commercial preparations have activity against HIV; however, it is believed that this antiretroviral activity is not due to the HCG itself, but due to other substances--impurities in the commercial product--which are sometimes associated with it. On March 16th a research team at New York University, Harvard Medical School, and the National Institutes of Health announced the purification and identification of three enzymes with anti-HIV activity from the urine of pregnant women, and also found related anti-HIV substances in human milk and some animal products. (1)
Dr. Robert Gallo, of the Institute of Human Virology in Baltimore, has also been working on a separate project to identify one or more antiretroviral substances found in the urine of women in the first weeks of pregnancy (2) (see "New Approaches to HIV Treatment: Interview with Robert Gallo, M.D.," AIDS TREATMENT NEWS #285, December 19, 1997).
If these results are confirmed, they could lead to new strategies for developing antiretroviral drugs.
References:
1. Lee-Huang S, Huang PL, Sun Y and others. Lysozyme and Rnases as anti-HIV components in beta-core preparations of human chorionic gonadotropin. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA March 16, 1999; volume 96, issue 6, pages 2678-2681.
2. Lunardi-Isandar Y, Bryand JL, Blattner WA and others. Effects of a urinary factor from women in early pregnancy on HIV-1, SIV and associated disease. NATURE MEDICINE April 1998; volume 4, number 4, pages 428-434. AIDS TREATMENT NEWS Issue #315, March 19, 1999
Source: AIDS TREATMENT NEWS Issue #315, March 19, 1999. AIDS Treatment News, Subscription and Editorial Office, P.O. Box 411256, San Francisco, CA 94141, TEL: 800/TREAT-1-2; 415/255-0588.
Testosterone effective for HIV-related wasting for up to 1 year
Hypogonadal men with AIDS wasting continue to gain lean body mass with testosterone therapy over the long term, according to a report by a Boston-based team.
Dr. Steven Grinspoon of Massachusetts General Hospital and colleagues randomly assigned 51 HIV-infected men with hypogonadism and AIDS wasting to testosterone enanthate (300 mg intramuscularly every 3 weeks) or placebo for 6 months. This was followed by an open-label extension, with the initial placebo group switched to testosterone, for another 6 months.
The subjects were assessed for caloric intake, body composition, exercise history, quality of life and hormonal and immunologic function. In addition, prostate evaluations were performed and prostate-specific antigen (PSA) levels were measured.
Thirty-four subjects completed the study. The results showed that subjects receiving testosterone injections for 12 months gained approximately 3.7 kg of lean body mass (LBM) compared to 1 kg in the group treated for only six months.
"Subjects initially randomised to placebo gained lean body mass (LBM) only after crossover to testosterone administration," the investigators report in the March issue of Clinical Infectious Diseases. The subjects initially receiving testosterone "...continued to gain LBM during the open-label administration...and had gained more LBM at 1 year than did subjects receiving testosterone for only the final 6 months of the study."
Side effects of treatment were minimal, and the researchers observed no new prostate nodules or increases in PSA levels in the subjects.
Based on these findings, Dr. Grinspoon's group recommends that standard maintenance doses of testosterone therapy be initiated in hypogonadal men with AIDS wasting. And treatment should be "...continued for at least 1 year, unless its use is specifically contraindicated as a result of prostate malignancy or other pre-existing condition."
Ref: Clin Infect Dis 1999;28:634-636.
Source: CDC HIV/STD/TB Prevention News Update
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6th Conference on Retroviruses and Opportunistic InfectionsJanuary 31 - February 4, 1999 - Chicago, IL
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MISCELLANEOUS REPORTS |
Author - Joel E. Gallant, M.D., M.P.H.
The Hopkins HIV Report - March 1999
In our issue devoted to coverage of last year's ICAAC [HHR, vol. 10, no. 6; Nov. 1998; p.1], I discussed the surprising new finding that many patients failing HAART therapy may have relatively little resistance to the failing drug regimen. A number of studies were presented in Chicago that support these findings. The most important data came from ACTG 343 [Havlir, et al., Abstract LB12]. This was one of three trials testing the induction-maintenance strategy, each of which demonstrated that "de-intensification" of a HAART regimen leads to virologic failure. In ACTG 343, patients who achieved viral suppression on a regimen of ZDV/3TC/IDV were randomised to continue triple-drug therapy or to switch to either ZDV/3TC or IDV monotherapy. As has been reported previously, 23% of those taking IDV or ZDV/3TC developed viral rebound compared to only 4% of those taking ZDV/3TC/IDV. Resistance testing was performed on nine isolates from patients failing IDV monotherapy and 17 isolates from patients failing triple therapy. None of the patients with viral rebound on IDV had resistance to any protease inhibitor. Duration of failure ranged from 1 to 3 months, and although viral loads tended to be low, they ranged from 1,000 to over 100,000 c/ml. Of the 17 patients failing triple-therapy, none had phenotypic resistance to protease inhibitors, and only one had a significant protease mutation by genotype analysis (M46L). However, 14 (82%) had the M184V mutation and phenotypic 3TC resistance. These findings cannot be explained by cessation of indinavir therapy, as most patients had detectable IDV levels.
In a presentation by Holder from Merck Research Labs [Abstract 492], IDV resistance was present in only 21% of patients failing ZDV/3TC/IDV in Merck 054 and in 22% of those failing IDV/EFV in Merck 067. 3TC resistance and EFV resistance were found in 74% and 92% of patients, respectively. Similarly, in the Trilege trial, another induction-maintenance trial, no ZDV or IDV resistance mutations were observed in 58 patients failing maintenance therapy with ZDV/3TC/IDV, ZDV/3TC, or ZDV/IDV [Descamps, et al., Abstract 493]. The M184V mutation associated with 3TC resistance was seen in most patients, including those on ZDV/3TC who were not failing therapy.
A number of hypotheses have been proposed to explain these surprising findings, none of which is entirely satisfactory. Nevertheless, these findings suggest that the practice of changing all the drugs in a failing regimen may not be necessary and that resistance testing could be used during early failure to identify which drugs should be changed and which should be continued. This would be welcome news, given the paucity of antiretroviral agents that are unique with respect to resistance. However, we should interpret these findings with caution, since currently available resistance assays are known to be insensitive to resistant mutants present in small quantities. It should be noted that while these findings are now consistent across three studies, we still don't know whether or not the strategy of selectively altering a failing regimen based on resistance data will be effective.
(c)1999. The Johns Hopkins University AIDS Service, Division of Infectious Diseases. Permission to use and reproduce portions of this newsletter is hereby granted provided that author and publication are fully credited and both copyright and permission notice appear with reprinted material. Inquiries may be directed to Mary Beth Hansen, Managing Editor. Website: Johns Hopkins AIDS Service.
Gender Difference in Nevirapine-Associated Rash
A study reported at the recent Chicago conference suggest that women are more likely to develop rash, especially severe rash, as a side effect of the anti-HIV drug nevirapine compared to men. Researchers looked at the medical records for 85 women and 176 men receiving nevirapine-containing anti-HIV regimens between 9/93 and 9/98. Overall, 26 people developed rash within the first 90 days of taking nevirapine, of whom twelve were women. Mild rashes were seen in four women and 13 men, whereas severe rashes were seen in eight women and one man.
In this study, rash was more likely seen in people with higher CD4+ cell counts (e.g. greater than 200), but was unaffected by differences in age, race or concurrent use of other medications. In other studies of nevirapine, severe rash was seen in only about 3% of people taking the drug. Overall, however, 85% of participants in studies of nevirapine have been men, so it is not clear how well this figure applies to women.
These recent findings underscore the need for including greater numbers of women in studies of new therapies, so that when gender differences exist they are readily apparent from early study results. Additionally, they suggest that women using nevirapine take special care to watch out for the development of rash and perhaps to use pre-treatment, such as Benadryl(r) [Ed. - antihistamine or alternatively a systemic corticosteroid as cover], to minimise the risk. It is common when using nevirapine to start therapy at half the standard dose for the first few weeks to minimise the risk of rash. Based on this new data, this practice may be even more important in women than in men.
Source: PI Perspective 27, April 1999
Neurology Update
Justin C. McArthur, M.P.H., M.B.B.S.
The Hopkins HIV Report - March 1999
Declining Incidence of Neurologic Complications of HIV Disease
A study from the Multicenter AIDS Cohort Study (MACS) [Sacktor, et al., Abstract 410] demonstrates declines of at least 50% in the incidence of HIV dementia, toxoplasmosis, cryptococcal meningitis, progressive multifocal leukoencephalopathy (PML), and primary CNS lymphoma since the introduction of highly active antiretroviral therapy (HAART) in 1996. This study parallels data from other cohorts demonstrating dramatic declines in the incidence rates of various AIDS-related illnesses and improvements in survival. While these data confirm encouraging trends in the morbidity and mortality of HIV infection, there still remains the potential that the enlarging pool of people living with AIDS may represent a group which is "neurologically vulnerable" for neurologic disease, with the CNS serving as a sanctuary for partially suppressed HIV replication.
Cidofovir for the Treatment of PML
PML remains a terrifying neurological complication which has proved refractory to many therapies including cytosine arabinoside and topotecan. Positive effects of potent antiretroviral regimens have been seen, both in terms of survival and incidence rates of PML. Cidofovir is currently under study for treatment of PML by the AIDS Clinical Trials Group (ACTG 363) and in a European study. Gasnault reported the effects of open label cidofovir on survival for patients with PML [Abstract 417]. Thirteen of 35 patients with PML received cidofovir. All were receiving potent antiretroviral combination therapy. The median survival for cidofovir recipients was 281 days compared to 215 days in those who only received antiretrovirals. No improvement in neurological function was noted, although 6/10 patients showed reversion of CSF JC virus DNA positivity.
The in vitro efficacy of cidofovir against JC virus remains controversial. Although earlier studies presented in Geneva suggested a positive effect of cidofivir, this open label study does not demonstrate a significant survival advantage. The results of larger ongoing studies are anticipated early in 2000.
Antiretroviral Drug Levels in CSF
A number of studies have examined the pharmacokinetics of available antiretrovirals within the cerebrospinal fluid. In an extension of previously presented data from the Prometheus Study (comparing the efficacy of virological suppression in plasma and CSF of ritonavir (RTV)/saquinavir (SQV) vs. RTV/SQV/d4T), Gisolf and colleagues demonstrated that HIV in CSF remained detectable in 9/14 individuals even after 48 weeks of RTV/SQV compared to only 1/13 on the d4T-containing arm [Abstract 403]. CSF concentrations of RTV/SQV were undetectable. In contrast, Polis and co-workers found that 7/15 patients had CSF viral loads >50 c/ml at 2 months by 6 months all 15 patients had undetectable CSF viral loads after initiation of regimen of ZDV, 3TC, nevirapine, and indinavir (IDV) [Abstract 404]. Indinavir was detectable in all patients, with levels ranging from 27 to 228 nanograms/ml.
Despite the potency for virological suppression in plasma, RTV/SQV alone do not adequately penetrate into the CSF. IDV does appear to penetrate into the CSF and durable virological suppression can be obtained. Interestingly, however, in the Polis study virological suppression appeared to be slower in the CSF than in plasma, since 4/11 patients had detectable HIV in CSF at the two month time point.
CSF HIV RNA and Clinical Outcomes
Marra and colleagues examined HAART-induced changes in CSF and plasma HIV RNA levels and neuropsychological test performance [Abstract 408]. Improvements in neuropsychological test performance after HAART paralleled CSF virological response. This study provides further evidence that neurological function can improve with potent combination antiretroviral regimens, and suggests that CSF HIV RNA levels may serve as a surrogate marker for neurologic involvement.
Pathogenesis of Dementia
Previous pathological and radiological studies have confirmed significant perturbation of the blood-brain barrier in patients with HI V-associated dementia. The metalloproteinases may target proteins critical for the maintenance of the blood brain barrier, including collagen type 4. Conant and colleagues demonstrated an elevation in metalloproteinase-9 and the preforms of both MMP-2 and 7 in CSF from patients with HIV dementia [Abstract 282]. Ghorpade detected production of MMP-9 in brain tissue from patients with HIV dementia [Abstract 283]. Both of these studies suggest a potential role for increased production of select matrix metallo-proteinases in HIV dementia. The local release of MMPs into the brain may lead to perturbation of the blood-brain barrier which could facilitate the entry of infected cells or expose the brain to potentially toxic proteins in the systemic circulation.
Viral Load and Resistance Mutations in Brain Tissue
Lanier presented data on brain tissue HIV RNA levels from patients with and without HIV dementia. Overall, HIV RNA levels in different brain regions tended to be higher in patients with dementia [Abstract 298]. There was no clear cut relationship, however, between the actual levels and the clinical severity of neurologic disease. Discrepancies in the specific reverse transcriptase mutations which have been associated with zidovudine resistance were identified by genotyping in different brain regions. In general, however, when resistance mutations were detected in the periphery, similar mutations were noted in the CNS.
At this point, resistance mutations in CSF and brain appear to develop in parallel with those in blood, that is, there is concordance among the different compartments. The relatively weak relationship between levels of HIV RNA in brain tissue and the expression of neurologic disease suggests that indirect mechanisms, including local production of macrophage activation products, may be critical determinants of neurologic damage.
(c)1999. The Johns Hopkins University AIDS Service, Division of Infectious Diseases. Permission to use and reproduce portions of this newsletter is hereby granted provided that author and publication are fully credited and both copyright and permission notice appear with reprinted material. Inquiries may be directed to Mary Beth Hansen, Managing Editor. Website: Johns Hopkins AIDS Service.
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ATP DR FAX SYMPOSIUM IIIOPTIMISING FIRST-LINE AND SALVAGE THERAPY: Pharmacological Barriers to Effective Treatment, Drug Level Monitoring, Drug Synergism and Novel Treatment Strategies
A ONE DAY SYMPOSIUM
AIDS Treatment Project and the 'Doctor Fax' is hosting a one day symposium focusing on salvage therapy, individualising treatment and the use of therapeutic drug monitoring. As with previous ATP Dr Fax Symposia, this is an international meeting intended for HIV treating clinicians, researchers, health commissioners and purchasers.
DATE: Thursday 13 May 1999
VENUE: Royal College of Physicians, London
CHAIR: David Back, University of Liverpool
INVITED SPEAKERS INCLUDE:
Richard Hoetelmans (The Netherlands), Joep Lange (The Netherlands), Ceppie Merrie (UK), Schlomo Staczewski (Germany)
Programme will include discussions on optimising first-line and salvage therapy through mega- HAART, role of hydroxurea, immune base therapy with HAART, and maximising protease inhibitor synergism. Therapeutic monitoring will be discussed in relation to routine patient management, paediatric care and pregnancy and individuals with hepatic and renal dysfunction.
Places are strictly limited - to register or receive an information pack, please contact Kimberly Gray, Events & Projects Coordinator, on 0171 407 0777 or kimberlyg@atp.org.uk
AIDS Treatment Project St Stephens House Tel: 0171 407 0777 Fax: 0171 403 4262 Email: admin@atp.org.uk |