Medical Consultant
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ANTIRETROVIRALS
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Paul Blanchard, ATP.
On April 15, 1999, the U.S. Food and Drug Administration granted accelerated approval to amprenavir, a new protease inhibitor in the same class (peptidomimetic) as currently licensed protease inhibitors. Amprenavir has been approved in the U.S. for use in children age four and older and in adults in combination with other antiretrovirals for HIV infection.
The FDA based its approval for amprenavir on 24-week data from two ongoing controlled clinical studies involving more than 700 patients. Results from these trials showed a decrease in viral load and an increase in CD4 cell counts in patients taking amprenavir in combination with other antiretrovirals. Acceptable results were seen in both treatment naive patients and also in those who had previously received antiretroviral therapy with reverse transcriptase inhibitors only.
The recommended dose of amprenavir is eight 150-mg capsules twice daily with three times daily dosing for some children, with or without food, but high fat meals should be avoided. This approval is only for the use of amprenavir in combination with other antiretroviral drugs. Amprenavir should not be used alone due to the rapid emergence of drug resistant HIV to monotherapy.
In clinical studies to date the majority of adverse events have been of mild to moderate intensity. According to data from Glaxo Wellcome's safety database, 28% of patients developed rash, 25% felt numbness around the mouth, and more than half suffered some mixture of nausea, vomiting, and diarrhoea (Pedneault et.al. [abstract 386] 6th Retrovirus Conference, Chicago 1999). The most frequently reported adverse events were nausea, diarrhoea, vomiting, rash, and perioral paraesthesia. Severe and life-threatening skin reactions, including Stevens-Johnson syndrome, have occurred in one percent of patients treated with amprenavir although less severe skin reactions and rashes may occur in up to 11 percent of patients. As with other protease inhibitors, amprenavir may be associated with acute haemolytic anaemia, diabetes mellitus, and hyperglycaemia. In both Phase III studies severe laboratory abnormalities occurred infrequently.
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Amprenavir is currently available through an expanded access scheme in the UK. Physicians wishing to access the drug should contact Una Loughrey at Glaxo Wellcome (0181 990 2900).This programme will continue until amprenavir is licensed and commercially available in the UK.
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In order to be effective, combination anti-HIV therapy (HAART) must be taken according to a strict schedule. If doses are missed or taken incorrectly, drug resistance may develop and the benefits of treatment may diminish. For patients taking these drugs, however, maintaining such challenging schedules for long periods of time can be very taxing. This conflict has prompted researchers to study the effects of so-called "drug holidays" in patients taking HAART. In a study conducted in Paris at the Hôpital Pitié-Salpêtrière, Dr. Christina Katlama and colleagues found that interrupting therapy for a period of four weeks showed no harmful effect on treatment efficacy once therapy was resumed. The results of this study appear in the current issue of AIDS.
The COMET study enrolled ten HIV-positive patients with viral loads of at least 5,000 copies and CD4+ counts above 150 cells. None of the subjects had taken antiretrovirals before, nor had they experienced an AIDS-defining illness. Each of the subjects received HAART for a period of 28 days or longer before interrupting their treatment. After 28 days without treatment, the subjects resumed their initial combination.
The subjects' viral load decreased during the first phase of treatment, but quickly rebounded within four to seven days of stopping therapy, according to Dr. Katlama's team. However, once therapy was resumed, the subjects' viral load dropped to levels similar to those observed during the first month of therapy. In addition, no signs of drug resistance were observed. Finally, after one year, all subjects who had continued triple combination therapy for at least four months maintained viral loads below 200 copies/ml.
Based on these results, the researchers conclude that "interruption of efficient ART for a month has no deleterious effect on the efficacy of therapy once it is reinitiated." That said, however, the French team warns that their findings do not mean drug holidays are beneficial. As well, stopping therapy for a longer period of time might still erase the initial benefits of therapy, according to the researchers.
There are several points to consider when interpreting the results of this trial. Firstly, the data state that patients had viral loads below 200 copies after one year, although current technology allows us to detect viral loads as low as 50, or even 20 copies. It would therefore have been interesting to see if a more sensitive viral load test would have detected differences in viral levels measured before stopping and after resuming therapy. As well, none of these patients had had an AIDS-defining illness and all had CD4+ counts above 150 cells. Results in more severely immune compromised patients could differ. Finally, none of these patients had taken antiretroviral drugs previously. The effect of drug holidays on treatment-experienced patients might not be as harmless.
Ref: AIDS 1999;13:677-683.
"From Community AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca"
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No resistance-conferring mutations were observed in the HIV-reverse transcriptase (RT) and protease regions after the interruption of therapy. Based on these findings, Dr. Katlama's group concludes that a "...complete interruption of efficient ART for a month has no deleterious effect on the efficacy of therapy once it is reinitiated." They stress, however, that these findings do not mean that treatment interruption benefits the patient, or that a longer treatment hiatus will not "erase" the benefits of previous therapy. Caution has to be observed in interpreting these findings. One interruption only was studied and the results from a series of interruptions are unlikely to be so benign. It must also be asked if the genotypic methods used in this study were efficient enough to detect the minority subspecies which may be encouraged by this approach. |
Imaging characteristics of indinavir calculi
Abstract:
Purpose: Indinavir sulfate is an effective protease inhibitor of the human immunodeficiency virus type 1. Use is associated with a significant incidence of crystallisation and stone formation in the urinary tract, and these calculi are not visible on plain radiographs. Previously all urinary stones, including uric acid and matrix, were believed to be radiodense on computerised tomography (CT). We conducted a retrospective study to evaluate the radiographic appearance of indinavir calculi.
Materials and Methods:
Retrospective chart review of 36 patients taking indinavir sulfate and presenting with renal colic was performed with attention to presentation, urinalysis, radiographic evaluation and management. Specifically, imaging characteristics on CT were addressed.
Results:
All patients complained of ipsilateral flank pain and 35 had nausea and/or vomiting. Of 30 patients with dysuria or urgency the majority had haematuria, and most had pyuria and/or proteinuria. No stones were visualised on abdominal radiography. Diagnosis was confirmed on 1 of 13 excretory urograms and 4 of 11 renal ultrasounds. None of 12 CT scans was diagnostic of renal lithiasis.
Conclusions:
Indinavir sulfate is a protease inhibitor with poor solubility and significant urinary excretion. Crystallisation and stone formation are demonstrated in as many as 20% of patients taking the medication. Most patients present with flank pain, nausea or vomiting and haematuria. Previously CT was thought to identify all urinary calculi with clarity but it cannot reliably confirm the presence of indinavir calculi.
Ref: Schwartz,B.F., Schenkman,N., Armenakas,N.A., Stoller,M.L.: J.Urol.,161 (4):1085-1087 (1999 Apr).
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Frequent presentation to Accident and Emergency departments requires clear guidance on diagnosis and management of indinavir related kidney problems. Current diagnosis should include an IVU radiograph. Management is by increasing fluid intake (i.v. and oral) with analgesic cover. Indinavir dosing should continue unless pain is severe or time to resolution is prolonged (more than 48 hours). |
The relative replicative fitness of human immunodeficiency virus type 1 (HIV-1) mutants selected by different protease inhibitors (PIs) in vivo was determined. Each mutant was compared to wild type (WT), NL4-3, in the absence of drugs by several methods, including clonal genotyping of cultures infected with two competing viral variants, kinetics of viral antigen production, and viral infectivity/virion particle ratios. A nelfinavir-selected protease D30N substitution substantially decreased replicative capacity relative to WT, while a saquinavir-selected L90M substitution moderately decreased fitness. The D30N mutant virus was also out competed by the L90M mutant in the absence of drugs. A major natural polymorphism of the HIV-1 protease, L63P, compensated well for the impairment of fitness caused by L90M but only slightly improved the fitness of D30N. Multiply substituted indinavir-selected mutants M46I/L63P/V82T/I84V and L10R/M46I/L63P/V82T/I84V were just as fit as WT. These results indicate that the mutations which are usually initially selected by nelfinavir and saquinavir, D30N and L90M, respectively, impair fitness. However, additional mutations may improve the replicative capacity of these and other drug-resistant mutants. Hypotheses based on the greater fitness impairment of the nelfinavir-selected D30N mutant are suggested to explain observations that prolonged responses to delayed salvage regimens, including alternate PIs, may be relatively common after nelfinavir failure.
Ref: Martinez-Picado J, Savara AV, Sutton L, D'Aquila RT. J Virol 1999 May;73(5):3744-3752.
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Due to substantial similarities amongst the class of peptidomimetic protease inhibitors it is unlikely that there will be substantial differences in accumulated HIV mutations conferring resistance to this group of PI's. This study does not account for compensatory mutations in gag/pol cleavage sites which have been shown to overcome defects in processivity and viral fitness. |
The HIV/AIDS Treatment Information Service announces that the Pediatric Working Group has updated the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection as of April 15th, 1999. Information on the use of abacavir (Ziagen), a nucleoside reverse transcriptase inhibitor, in combination with other approved therapies has been included in this version of the guidelines.
There have also been changes in Table 8 terminology for "Choice of Therapy" categories. You can download the paediatric guidelines from the ATIS web site: http://hivatis.org/
ATIS has redesigned the site to allow for easier searching of guidelines. All current versions of the treatment guidelines can be found under the "Current Treatment Guidelines Library." Previous versions of the guidelines are stored in the archived library. We hope that this makes finding information on the latest treatment guidelines easier.
Source: A news update from the HIV/AIDS Treatment Information Service (ATIS)
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METABOLISM
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Researchers from the Boston University School of Medicine investigated the prevalence of abnormal body-fat distribution in HIV-1-infected children. The authors based their data on a survey sent to all U.S. paediatric AIDS Clinical Trial Groups and National Institute of Child Health and Human Development sites between March and August of last year. Of the 55 sites responding, 16 reported at least one instance of abnormal fat distribution. A total of 1,644 out of 2,713 children on antiretroviral therapy were taking protease inhibitors. One percent experienced abnormal fat distribution; 0.4 percent of those who did were not taking protease inhibitors, while 1.5 percent were taking the drugs. Nearly two-thirds of the children with abnormal body fat were female, more than 40 percent were African-American, and the average age was 10.9 years. At the time of reporting, the mean viral load in children with abnormal body fat was 98,000 copies, and the mean CD4-cell count was 367 cells. The researchers note that future research should present a standardised definition of abnormal body fat distribution, a comparative analysis of risk factors, evaluations of endocrine abnormalities, and correlations with particular therapies.
Ref: Babl F E; Regan A M, Pelton, Stephen I. The Lancet. Vol. 353, No. 9160, P. 1243. (10/04/99). Source: CDC HIV/STD/TB Prevention News Update
Mexican researchers present the case of a 46-year-old man who used liposuction to treat the lipodystrophy that developed as a result of his use of saquinavir and nelfinavir. The man, who was diagnosed with HIV in 1989, had been taking a combination of zidovudine, zalcitabine, and saquinavir for about a year when he observed a continued thickening of his neck. The cocktail was switched to nevirapine, nelfinavir, and didanosine, but more than a year later he developed a buffalo hump as a result of abnormal fat accumulation in the area. Until something else is developed, the researchers note that liposuction may be an acceptable treatment for abnormal fat deposits, which may play a role in non-compliance with antiretroviral regimens.
Ref: Ponce-de-Leon S; Iglesias M; Ceballos J; et al. The Lancet Vol. 353, No. 9160, P. 1244; (10/04/99) Source: CDC HIV/STD/TB Prevention News Update
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TRANSMISSION
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Sperm washing may permit safer conception for HIV-discordant couples
Recent studies in the United Kingdom suggest that "sperm-washing" followed by artificial insemination may be the safest way for HIV-discordant couples to have a child. Dr. Jill W. Gilmour, of the Chelsea Westminster Hospital, and colleagues collected data on spermatozoa, non-sperm cells, and plasma fractions from semen samples taken from HIV-positive men. Of the three groups, spermatozoa had no significant levels of CD4, CCR5 or CXR4, and all spermatozoa were negative for viral RNA or proviral DNA. These findings indicate that the "...primary reservoir for HIV RNA in semen is the seminal plasma and [non-sperm cells]." And by washing the spermatozoal fraction, HIV RNA levels can be reduced to below detectable levels, which ranged from between 20 and 80 copies/mL in the samples.
Based on these data, Dr. Gilmour's group would therefore "...recommend 'sperm-washing' followed by insemination as a safer alternative to natural conception for HIV-discordant couples wishing to have children." The researchers concluded that seminal plasma and non-sperm cells were the main reservoirs of HIV RNA in semen, and they noted that by washing the spermatozoal fraction, HIV RNA levels can be decreased to below detectable levels.
Ref: AIDS 1999;13:645-651. Source: CDC HIV/STD/TB Prevention News Update
The European Commission reports that as of year-end 1997, there were 95 confirmed and 191 possible cases of occupationally acquired HIV throughout the world. A total of 52 definite and 114 possible infections were reported in the United States. The findings, which are reported in the March issue of Eurosurveillance, are up from the 16 definite cases and 47 possible cases the European Commission announced two years ago.
Ref: Eurosurveillance 1999;4:29-32. Source: CDC HIV/STD/TB Prevention News Update
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IMMUNOLOGY
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The effects of highly active antiretroviral therapy on cytokine imbalances associated with HIV-1 infection have not been characterised. Using single cell analysis by flow cytometry, we show that a significant recovery in the frequency of IL-2-producing cells was only observed in patients with a sustained control of viral replication and that the overexpanded CD8 T cell population of CD28- IFN-gamma + cells was not significantly reduced after 1 yr of effective therapy. Moreover, a detrimental role of IL-4 is suggested by the association between an enhanced proportion of IL-4-producing cells within the CD4 and particularly the CD8 subset and viral load rebound. Finally, the kinetics of changes of cell subsets assessed for simultaneous production of different cytokines supports the view that cell reconstitution during highly active antiretroviral therapy is initially due to redistribution of terminally differentiated cells, followed by peripheral expansion of less differentiated ones and a late progressive increase of the proportion of functionally defined naive/memory precursor lymphocytes. These data bring new support for the role of cytokine imbalances in AIDS pathogenesis and may be relevant for the definition of immunointervention targets.
Ref: Sousa AE, Chaves AF, Doroana M, Antunes F, Victorino RM. J Immunol 1999 Mar 15;162(6):3718-26.
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OPPORTUNISTIC EVENTS
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Results of a large observational study indicate that discontinuation of Pneumocystis carinii pneumonia (PCP) prophylaxis led to no new cases of PCP among HIV-1-infected patients once they started highly active antiretroviral therapy (HAART). Based on these findings, Dr. Peter Reiss of the University of Amsterdam in the Netherlands and other members of the EuroSIDA Study Group conclude that primary PCP prophylaxis may be safely discontinued by patients on HAART who have CD4 lymphocyte counts higher than 200/µL.
In the April 17th issue of the Lancet, Dr. Reiss' group reports the results of a "...person-years analysis of the rate of discontinuation of PCP prophylaxis and of the incidence of PCP after the introduction of HAART into clinical practice from July, 1996." The EuroSIDA Study Group is an ongoing, prospective cohort study of 7333 HIV-1-infected patients from 52 centers in Europe and Israel.
The researchers found that 319 patients discontinued primary PCP prophylaxis and 59 patients discontinued secondary PCP prophylaxis at a median of 10 months after they started HAART. "At discontinuation for primary and secondary prophylaxis, respectively, the median CD4 lymphocyte counts were 274 cells/µL and 270 cells/µL," they report. For both patient groups, the median HIV-1 RNA load at PCP prophylaxis discontinuation was 500 copies/mL. Dr. Reiss' group found that during "...247 person-years of follow-up, no patient developed PCP."
Although the results suggest that primary PCP prophylaxis is not necessary for patients on HAART with CD4 lymphocyte counts above 200 cells/µL, "[l]onger follow-up is needed to confirm a similarly low risk for stopping secondary PCP prophylaxis."
Ref: Lancet 1999;353:1287,1293-1298. Source: CDC HIV/STD/TB Prevention News Update
AIDS-related wasting is a potentially devastating condition characterised by a body weight loss of 10% or more, sometimes accompanied by persistent diarrhoea. Weight loss, whether it fits the definition of wasting or not, is a concern for anyone living with HIV. Ideally, treatments designed to combat HIV-related wasting help to build lean body mass, as opposed to fat. Lean body mass is crucial for maintaining good health. Several strategies exist to help increase body weight including appetite stimulants, growth hormones and anabolic steroids. Now, a study conducted in San Francisco has produced impressive results by combining the anabolic steroid oxandrolone (Oxandrin) and progressive resistance exercise (PRE). The findings of this study appear in the April 14th issue of the Journal of the American Medical Association.
Dr. Mark Hellerstein of the University of California at San Francisco/Berkeley studied 29 HIV-positive men who had suffered involuntary weight loss. The subjects were randomly assigned to two groups. Both groups received a 100 mg dose of testosterone once a week and participated in a strength building exercise program three times weekly. In addition, one group received 20 mg oral oxandrolone per day, while the other received a placebo.
Improvement was observed in both groups after two months. However, subjects in the oxandrolone group experienced significantly higher weight gain and increases in lean body mass. On average, those taking the steroid gained 15 pounds of muscle, while those on placebo gained only half that amount. As well, the increase in body weight was accompanied by "tremendous increase in strength," according to Dr. Hellerstein. Finally, the use of protease inhibitors did not affect gains in lean body mass or strength.
Ref: JAMA 1999;281:1282-1290. "From Community AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca
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At follow-up, Dr. Strawford's group found that all 22 subjects who completed the study had "significant nitrogen retention and increases in [lean body mass], weight, and strength." However, the "gains were significantly greater in the oxandrolone group than in the placebo group." Treated subjects also exhibited significant declines in HDL cholesterol compared with the placebo group. Whether or not the subjects were also receiving a protease inhibitor did not appear to affect the results. "This is an important point because weight gain after initiation of protease inhibitor therapy usually takes place through the accumulation of body fat, but our goal in patients with HIV-related weight loss is to build up the lean tissue," senior investigator Dr. Mark K. Hellerstein commented in a press release. "Perhaps the most important finding of this study is that extremely high dosages of androgens were not required for a significant beneficial interaction with [progressive resistance exercise]," Dr. Strawford's group points out in the paper. The 20-mg daily dose of oxandrolone has previously been shown to be well-tolerated with long-term use, the investigators say. |
Dr. Sylvie Chevret and colleagues at the Hopital Saint-Louis in Paris. Dr. Chevret's team evaluated the usefulness of measuring CMV antigenaemia in a cohort of 214 HIV-infected patients. The subjects had a median baseline CD4 cell count of 36/µL and most had experienced an AIDS-defining condition.
"Multivariate analysis revealed that only positive baseline CMV antigenaemia assays...and CD4 cell counts...were associated with CMV disease," they report in the April issue of Clinical Infectious Diseases. They also found that positive results on baseline CMV antigenaemia assay were associated with increased risk of death. In addition, mortality risk increased with increasing CMV antigenaemia levels.
Based on these findings, they conclude that the "...presence and level of CMV antigenaemia is directly related to the risk of developing CMV disease and death in patients with AIDS."
They suggest that the CMV antigenaemia assay may be useful in CMV disease prevention trials and in prolonging survival in AIDS patients, by identifying patients who are at risk for CMV disease, and who should receive CMV prophylaxis, but do not have symptoms.
Ref: Clin Infect Dis 1999;28:758-763. Source: CDC HIV/STD/TB Prevention News Update
For local treatment of cytomegalovirus retinitis in patients with AIDS, intraocular ganciclovir implants are generally effective. However, the procedure does not treat or prevent other symptoms of cytomegalovirus infection. A team of U.S. scientists evaluated the treatment in 377 patients with AIDS and unilateral cytomegalovirus retinitis. One group of patients was given intravenous ganciclovir alone, while a second group was given the implant and oral ganciclovir, and a third group was given placebo in addition to the implant. The main outcome was new cytomegalovirus disease, contralateral retinitis, or biopsy-proved extraocular disease. After six months, new disease was seen in 44.3 percent of the group that received the placebo and the implant, versus 24.3 percent in the group given both oral ganciclovir and the ganciclovir implant, and 19.6 percent among those receiving intravenous ganciclovir. Oral ganciclovir cut the overall risk of new cytomegalovirus disease by 37.6 percent during the 12 months of the study, compared to placebo. Among those patients who were taking protease inhibitors, the incidence of new cytomegalovirus disease was low and about the same in all three treatment groups. The scientists noted that the advance of retinitis in the eye that received the first implant was impeded when oral ganciclovir was added to therapy, versus placebo. In addition, oral and intravenous ganciclovir cut the risk of Kaposi's sarcoma by 75 percent and 93 percent, respectively, versus placebo.
Source: CDC HIV/STD/TB Prevention News Update
Abstract
Background: The intraocular ganciclovir implant is effective for local treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (AIDS), but it does not treat or prevent other systemic manifestations of cytomegalovirus infection.
Methods: Three hundred seventy-seven patients with AIDS and unilateral cytomegalovirus retinitis were randomly assigned to one of three treatments: a ganciclovir implant plus oral ganciclovir (4.5 g daily), a ganciclovir implant plus oral placebo, or intravenous ganciclovir alone. The primary outcome measure was the development of new cytomegalovirus disease, either contralateral retinitis or biopsy-proved extraocular disease.
Results: The incidence of new cytomegalovirus disease at six months was 44.3 percent in the group assigned to the ganciclovir implant plus placebo, as compared with 24.3 percent in the group assigned to the ganciclovir implant plus oral ganciclovir (P=0.002) and 19.6 percent in the group assigned to intravenous ganciclovir alone (P<0.001). As compared with placebo, oral ganciclovir reduced the overall risk of new cytomegalovirus disease by 37.6 percent over the one-year period of the study (P=0.02). However, in the subgroup of 103 patients who took protease inhibitors, the rates of new cytomegalovirus disease were low and of similar magnitude, regardless of treatment assignment. Progression of retinitis in the eye that initially received an implant was delayed by the addition of oral ganciclovir, as compared with placebo (P=0.03). Treatment with oral or intravenous ganciclovir reduced the risk of Kaposi's sarcoma by 75 percent (P=0.008) and 93 percent (P<0.001), respectively, as compared with placebo.
Conclusions: In patients with AIDS and cytomegalovirus retinitis, oral ganciclovir in conjunction with a ganciclovir implant reduces the incidence of new cytomegalovirus disease and delays progression of the retinitis. Treatment with oral or intravenous ganciclovir also reduces the risk of Kaposi's sarcoma.
Ref: Martin, Daniel F.; Kuppermann. Baruch D.; Wolitz, Richard A.; et al. New England Journal of Medicine Vol. 340, No. 14, P.1063; (08/04/99).
Abstract
Purpose: To determine anatomic and visual acuity outcomes of posterior segment complications after ganciclovir implant surgery.
Methods: We reviewed the medical records of 63 patients with acquired immunodeficiency syndrome who had active cytomegalovirus retinitis in 82 eyes and who underwent 110 consecutive ganciclovir implant procedures. Preoperative and postoperative visual acuity, type of postoperative complication, treatment, and lines of visual acuity change were determined.
Results: Thirty_eight eyes of 19 patients had bilateral ganciclovir implant procedures, and 25 eyes of 19 patients underwent two Or more ganciclovir implant procedures. Thirteen (12%) of 110 ganciclovir implant procedures developed posterior segment complications: rhegmatogenous retinal detachment in six, vitreous haemorrhage in four, endophthalmitis in two, and cystoid macular oedema with epiretinal membrane in one. Treatment included pars plana vitrectomy with silicone oil in two cases and without silicone oil in three cases, scleral buckling in one, intravitreal antibiotic injection in two, and laser photocoagulation in two. Overall, median visual acuity was 20/25 preoperatively. Median follow_up was 6 months for all eyes and 7 months for eyes with complications. Postoperative median visual acuity was 20/25 for eyes without complications vs 20/40 at 1 month, 20/60 at 3 and 6 months, and 20/100 at 12 months in eyes with complications (P <.001). More eyes with than without complications lost 2 or more lines of visual acuity (P <.001).
Conclusion: Postoperative complications occurred in 12% of the ganciclovir implant procedures and were associated with decreased visual acuity despite treatment.
Ref: Lim,J.I., Wolitz,R.A., Dowling,A.H., Bloom,H.R., Irvine,A.R., Schwartz,D.M. Am.J.Ophthalmol.,127 (3):288_293 (1999 Mar)
Purpose: To describe the risks, benefits, and recommended use of the ganciclovir implant for the treatment of human immunodeficiency virus related cytomegalovirus (CMV) retinitis in the era of potent antiretroviral therapy.
Methods: A panel of physicians with expertise in the use of the ganciclovir implant and in the management of CMV retinitis was convened by the International AIDS Society, USA. The panel reviewed and discussed available data, and developed recommendations for the use of the ganciclovir implant, the surgical technique, and related management issues. Recommendations were rated according to the strength and quality of the supporting evidence.
Results: The effect of potent antiretroviral therapy on the immunologic status of patients with human immunodeficiency virus disease has changed the manifestation and course of CMV retinitis in many patients. The clinical management of CMV retinitis and the role of the ganciclovir implant are thus changing. Factors in the decision to choose the ganciclovir implant include the patient's potential for immunologic improvement, location and severity of CMV retinitis, and the risks and costs associated with implantation and concomitant oral ganciclovir therapy.
Conclusions: The ganciclovir implant is safe and effective for the treatment of CMV retinitis. The indications for its use should be modified to account for increased patient survival and the potential for CMV retinitis to be controlled by effective antiretroviral therapy. Optimal use of the ganciclovir implant and discontinuation of therapy in selected patients with improvement in immunity may result in better long-term visual outcomes.
Ref: Martin DF, Dunn JP, Davis JL et al Int AIDS Soc USA: Am.J.Ophthalmol.,127 (3):329 - 339 (1999 Mar).
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It should be noted that the dose of oral ganciclovir used in the Martin study was 4.5 g daily, this is higher than both the approved dose and the dose used in previous studies. In the subgroup of patients receiving potent antiretroviral therapy, those assigned to receive oral or intravenous ganciclovir did not have a significantly lower rate of occurrence of new cytomegalovirus infection than patients treated with the ganciclovir implant alone. This result reflects the overall reduction in the rate of cytomegalovirus disease in patients treated with potent antiretroviral agents, and it indicates that adjunctive therapy with oral ganciclovir may not be necessary in patients who have responded well to highly active antiretroviral therapy. Another important result is that there was a significantly higher rate of severe neutropaenia (defined as an absolute neutrophil count below 500 cells per cubic millimetre) among recipients of oral ganciclovir than among those receiving either placebo or, surprisingly, intravenous ganciclovir. This complication may limit the use of oral ganciclovir at effective doses for some patients. With the introduction of protease inhibitors, the incidence of cytomegalovirus retinitis has fallen substantially. There is also growing clinical evidence that patients with pre-existing lesions of cytomegalovirus retinitis can discontinue long-term prophylaxis against cytomegalovirus after the initiation of potent antiretroviral therapy. The immune reconstitution that permits the withdrawal of specific anticytomegalovirus therapy can occur in 12 weeks or less. Thus, aggressive anticytomegalovirus therapy may be needed only during the period immediately after diagnosis. Ganciclovir implants, on the other hand, continue to release the drug for up to eight months, and their implantation may lead to surgical complications that one would prefer to avoid, particularly in patients who will eventually need no anticytomegalovirus therapy. When choosing treatments for patients with cytomegalovirus retinitis, it is important, therefore, to distinguish between patients who have not previously received antiretroviral therapy and those in whom antiretroviral therapy has failed. Because patients who have not previously been treated with antiretroviral therapy may be candidates for the eventual discontinuation of prophylaxis against cytomegalovirus after immune reconstitution, it has been argued that a ganciclovir implant is not appropriate for initial management in such patients. The current study still points us in an appropriate direction for patients with cytomegalovirus retinitis in whom antiretroviral therapy has failed or for whom these drugs are not available. The combination of a ganciclovir implant with oral ganciclovir is not appropriate for everyone with cytomegalovirus retinitis, but for selected patients with persistently impaired immunity, it offers tremendous benefits until better options become available. |
Successful treatment of paediatric HIV-related CMV encephalitis reported
Swiss researchers report that combining ganciclovir treatment with highly active antiretroviral therapy can resolve the cerebral lesions and clinical symptoms of paediatric HIV-related cytomegalovirus encephalitis. Until now, only one case of successful treatment of paediatric HIV-related CMV encephalitis has been reported; however, Dr. Christoph Rudin, of the University Children's Hospital in Basel, and colleagues detail in April's Pediatric Infectious Disease Journal the second successful treatment of the disease. The researchers found that within weeks of receiving the new treatment, the subject's clinical and neurological symptoms improved remarkably. According to the researchers, the effectiveness of the treatment seems to rest on its interdisciplinary approach, which utilises social and psychiatric support in addition to the prescribed medical treatment.
Ref: Pediatr Infect Dis J 1999;18:382-386.