Medical Consultant
12 th World AIDS Conference28 June - 3 July 1998, Geneva, Switzerland
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12 th World AIDS Conference28 June - 3 July 1998, Geneva, Switzerland |
Conference Report - Part Three
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Double Protease Inhibitor Combinations |
The combination of indinavir and ritonavir has been attracting attention as a potentially potent and 'user-friendly' combination.
Dr. Hsu of Abbott Laboratories [abs. 22361] presented a pharmacokinetic study of the combination of indinavir and ritonavir (400 mg of each every 12 hours) which enrolled 13 men and 3 women who were HIV-negative; this is frequently done to get a preliminary look at the way drugs work in the body. The study goal was to determine whether lower -- and in the case of indinavir less frequent -- doses could be given without lowering blood levels. Lower blood levels generally mean less antiretroviral effect. 9 men and 1 woman actually completed the 17-day study; three discontinued because of side effects, while three others withdrew consent.
Because ritonavir inhibits metabolism of indinavir, the study found that the lower dose of indinavir remained in the blood stream longer, even when given with a regular meal. Currently, indinavir can only be taken with low-fat foods. It also showed that twice daily rather than 3-times daily dosing might be effective in combination with ritonavir. Key results showed :
38 patients were enrolled in the following three groups:
Group A: All ten patients who reached the 36-week mark were undetectable (<400). Seven of 9 patients who reached week 52 were undetectable on the sensitive viral load test (below 40 copies); with the remaining two having viral loads of 42 and 72 copies. Nine of 12 achieved CD4 cell increases of over 100 cells, which was somewhat surprising given a) that these are experienced patients and b) their viral loads are already undetectable. Studies have shown indinavir's ability to increase CD4 cell counts over time, so the addition of IDV may account for this increase. Results in this arm suggest that the immune system may still derive benefit from treatment changes even when viral loads are already below the limits of detection. This is not in itself a reason to switch from one suppressive regimen to another, but it does warrant further investigation.
Group B : All patients reached levels <400 by Week 12, with 8 of 9 patients who completed Week 32 going below 40 copies of HIV per mL. Six of these 18 patients did experience mild diarrhoea, which went away with out changing the RTV dose.
Group C : All patients experienced a viral load drop, but the researcher did not say what proportion reached undetectable. Two of the patients who had previously failed on indinavir maintained viral loads below 800 copies out to Week 32.
No cases of stones, flank pain or dysuria were seen in any group of this small study.
Adapted from coverage provided by Michael Giordano, M.D.
Source: www.thebody.com
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It should be noted that Workmans data was not randomised. This gives the possibility of an overestimation of the benefits of RTV-IND. However, the pharmacokinetic data establishing lower peaks and higher troughs of IDV is likely to translate to a lower risk of renal calculi, and lower risk of viral breakthrough due to the possibility of insufficient drug exposure when indinavir is used alone. Antiretroviral effect in this combination is likely to be reliant on the indinavir exposure hence lower doses of RTV may be used (some physicians are suggesting RTV 200mg/IND 800 mg twice daily, particularly if raised triglycer ides are seen). |
Saah et al presented the preliminary week 24 findings from a study of co-administration of IDV and NFV in PI-naive subjects with HIV RNA levels >30,000 copies/mL and CD4 cell count >100/mL [abs 22352]. The initial dosing was IDV 1000 mg and NFV 750 mg every 12 hours (q 12 h); the NFV dose was increased to 1000 mg q 12 h when steady-state pharmacokinetic evaluation showed lack of IDV effect on NFV levels. A regimen of NFV 1000mg q 12 h with IDV resulted in a 35% increase in NFV trough over the NFV 750-mg dose. Eleven (61%) of 18 patients receiving protocol therapy had suppression of viral load to <400 copies/mL after a median of 24 weeks; 6 of the 11 patients at week 24 had HIV RNA levels <50 copies/mL as assessed using Ultra Direct assay. Median CD4 cell count change from baseline to week 24 was 133/m L. Genotyping of viral isolates from 2 patients with virologic failure confirmed an isolated protease substitution at L90M.
The 16-week results from a phase II trial of dual PI combination therapy with RTV plus NFV in 20 PI-naive patients with median baseline viral load and CD4 cell count of 32,459 copies/mL and 325/m L, respectively, were reviewed by Gallant et al [Abs. 12207] . All subjects received RTV 400 mg q 12 h; cohort 1 (n=10) received NFV 500 mg q 12h and cohort 2 (n=10) received NFV 750 mg q 12 h. At 16 weeks, cohort 1 sustained a mean decline in plasma HIV RNA of 2.2 log 10 copies/mL and a mean increase in CD4 cell count of 202/mL. Cohort 2 demonstrated a mean decrease in viral load of 2.71 log 10 copies/mL and a mean rise in CD4 cell count of 37/m L. Viral load was <20 copies/mL in 1 subject from each cohort and <400 copies/mL in 4 and 6 subjects in cohort 1 and cohort 2, respectively.
The results of a clinical trial of the hard-gel capsule form of SQV in combination with RTV vs IDV in 257 PI-naive subjects with screening CD4 cell count and viral load of <300/m L and >100,000 copies/mL, respectively, were presented by Pedersen et al [abs. 12221]. Three treatment regimens were studied: IDV 800mg tid, RTV 600mg bid, or SQV/RTV 400mg bid. All patients received NRTIs in combination with PI agents. Only 1 2% of patients in the IDV arm had a prior AIDS diagnosis vs 23%-24% in the other 2 arms; mean baseline viral load and CD4 cell count were 4.7 log 10 copies/mL and 170/m L, respectively. At 6 months, 79% of patients in the IDV arm, 72% in the RTV arm, and 86% in the SQV/RTV combination arm had HIV RNA <200 copies/mL ( P =0.19). In antiretroviral-naive subjects, 82%, 64%, and 95% of patients in the IDV, RTV and SQV/RTV arms, respectively, had plasma HIV RNA <200 copies/mL at week 24. In the 64 treatment-naive subjects, the proportions with <20 copies/mL at 24 weeks were 3 2% in the IDV arm, 32% in the RTV arm, and 70% in the SQV/RTV arm ( P=.02).
The 72-week results of a clinical trial of RTV-SQV combination therapy in PI-naive subjects with baseline plasma HIV RNA and CD4 cell count of 4.63 log 10 copies/mL and 273/m L, respectively, were presented by Mellors et al [abs. 12295]. Nucleoside reverse transcriptase inhibitors were added for subjects whose viral load did not reach <200 copies/mL at 12 weeks. At week 72, more than 90% (86/96) had HIV RNA <200 copies/mL; more than half had been dose-reduced to RTV/SQV 400 mg bid at 24 weeks. Median CD4 cell increase was 188/mL at week 72. Of the 27 subjects who added NRTIs because of HIV RNA >200 copies/mL, 23 (85%) achieved viral suppression <200 copies/mL at week 72.
The 48-week results of the Prometheus study of an open-label dual PI regimen of RTV and SQV alone or in combination with d4T in 208 PI- and d4T-naive patients with mean baseline viral load and CD4 cell count of 4.3 log 10 copies/mL and 270/mL, respectively, were reviewed by Gisolf et al [abs. 12274]. Fifty percent of patients had had prior NRTI therapy; 25% of patients had a CD4 cell count <100/mL at entry. Sixty-four percent of patients in the RTV/SQV arm had HI V RNA <400 copies/mL at week 24 vs 87% in the RTV/SQV+d4T arm. At week 48, 79% of patients in the RTV/SQV arm had viral suppression <400 copies/mL vs 83% in the RTV/SQV+d4T arm. The CD4 cell count change from baseline was 130/m L in both arms at week 48. Although patients with prior NRTI experience required a longer duration of therapy to achieve suppression of HIV RNA <400 copies/mL vs naive patients, there was no statistical difference at week 48 in the proportion of subjects (naive and NRTI-experienced) with viral suppression <400 copies/mL. Sixteen patients (14 in the RTV/SQV arm, 2 in the RTV/SQV+d4T arm) required intensification to achieve HIV RNA <400 copies/mL by week 36; most added d4T+3TC. Since 19% of patients on the RTV/SQV arm required additional antiretroviral agents to achieve viral load <400 copies/mL, the durability of response provided by RTV/SQV with delayed addition of NRTIs vs the initially administered triple therapy RTV/SQV+d4T is not yet defined.
Other studies that focused on dual PI therapy strategies using RTV/SQV are detailed in abstracts 22390, 12313, and 12316.
Authors: Mary A. Albrecht, MD. Scott M. Hammer, MD.
Source: Adapted from "Essays From the Experts", JAMA HIV/AIDS Information Center
See Doctor Fax Issue 50 for details of the SPICE study presented by Dr Graeme Moyle.
Dual PI therapy with SQV-sgc plus NFV in combination with NRTIs is also evaluated in abstract 12314.
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It remains unclear if correct dosing of IDV+NFV has been identified; 61% below quantification at week 24 in naive patients is not particularly impressive if this is an on therapy analysis. More tolerability data are also needed. These criticisms may also be applied to the combination of RTV+NFV. Clearly RTV+SQV has the most robust data and longer period of experience with use. However, this combination, and probably all RTV combinations, are likely to suffer some degree of lipodystrophy and hypertrigyceridaemia limiting higher doses of RTV and longer term utility. Potent PI combinations including drugs other than ritonavir are clearly needed. At this stage SQV+NFV does not appear quite as potent as RTV+SQV. Dual protease inhibitor based regimens may be particularly useful in any patient needing a 2nd line combination, in NNRTI + 2NA failures and in those intolerant of nucleoside analogues (in combination with NNRTI s once the three way interaction is understood - data urgently needed). |
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NOVEL PROTEASE INHIBITOR DOSING SCHEDULES
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Twice Daily Nelfinavir Regimens: Petersen et al presented results from a phase III, open-label, multicentre trial of bid and tid NFV dosing in combination with d4T and 3TC in 278 3TC-naive patients with baseline plasma HIV RNA and CD4 cell count of 5.3 log 10 copies/mL and 388/ mL, respectively [abs. 12224]. The NFV dosing schedules of 750mg tid and 1250 mg bid were compared. Ninety-three percent of patients in both dosing regimens maintained HIV RNA <400 copies/mL at week 32; no serious drug-related adverse events occurred. Diarrhoea of moderate/severe intensity was reported in 12% and 13% of patients treated with the bid and tid NFV doses, respectively. Overall, the NFV bid regimen appears comparable with the standard tid NFV dosing with respect to efficacy and safety.
The 16-week results from a trial of IDV in a 1000 mg q 8 h schedule plus once-daily efavirenz (EFV) 600 mg q day vs an IDV 12 00 mg q 12 h regimen in combination with EFV 300 mg q 12 h in 71 PI- and NNRTI-naive patients with baseline plasma HIV RNA and CD4 cell count of >10,000 copies/mL and >100/m L, respectively, were presented by Isaacs et al [abs. 12290]. At week 16, 86% of patients in the IDV bid arm had HIV RNA levels <400 copies/mL vs 75% of patients in the IDV tid arm. Median changes in CD4 cell count at week 16 were 120/mL and 141/ mL in the IDV bid arm and IDV tid arm, respectively. Preliminary results suggest that the IDV bid dosing schedule provides comparable potency to that of the standard tid regimen.
Authors: Mary A. Albrecht, MD. Scott M. Hammer, MD.
Source: Adapted from "Essays From the Experts", JAMA HIV/AIDS Information Center
16 week results were presented from a randomised open-label study which included the comparison of saquinavir-sgc (SQV-sgc, Fortovase) 1200mg tid to SQV-sgc 1600mg bid [abs. 12314]. Both three times daily and twice daily SQV-sgc groups added 2 new NRTI's at commencement of PI dosing. All were naïve to protease inhibitors. A summary of results at week 16 showed that the percentage who had achieved a VL of <400 copies/mL was similar whether SQV-sgc was dosed tid or bid (79% vs 75%), CD4 changes were also similar (+ 122 cells/mm3 vs. +146 cells/mm3). A pharmacokinetic substudy demonstrated favourable saquinavir exposure of both the 1600mg bid and the 1200mg tid regimens. Viral load results using an Ultrasensitive assay (<50 copies/mL) were unfortunately not presented . This study is ongoing.
Author: Paul Blanchard, ATP.
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Patients appear to be voting in favour of BID regimens despite small, short-term data. Of particular caution should be the lack of data for comparison on time to failure. So far only the NFV study is large enough to have any real statistical meaning. In persons who can manage TID this may still remain a more secure choice than BID. For those prone to miss doses a change to BID seems a good short term option. |
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Potential Complications of Protease Inhibitor Use
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However, data presented at this meeting did not provide definitive proof that PIs cause the metabolic disturbances reported. There is some evidence that the events may be attributable to advancing HIV infection itself. There was also a paucity of data on the relative incidences of metabolic problems with specific PIs. Finally, as is expected given the immaturity of data, there is little guidance available for clinicians and patients looking for advice on how to treat these metabolic complications other than to simply put up with them if the HIV infection is being controlled by highly active antiretroviral therapy (HAART).
The lipodystrophy syndrome has several components, not all of which will be present in any one patient. The principal features are:
Table - Abdominal Visceral Fat Accumulation
| PI-na ïve | PI | PI+IAF* | |
| VAT/TAT ratio | 0.4 | 0.59 | 0.7 |
| VAT (cm 2) | 106 | 141 | 202 |
PI + IAF = Patients taking PIs who demonstrate increased abdominal fat
The basis for comparison in this table is the PI-naive group of patients with HIV disease. Compared to this group, patients on PIs have an increased VAT/TAT ratio with the highest ratio being in the PI-experienced patients with body composition changes. The VAT increases in each of the groups from 106cm 2 in the PI-naive treatment group to 202 in the PI-treatment group, demonstrating increased abdominal fat as well.
Cooper emphasised a number of times during his review that this is a progressive process with subtle changes early on in PI use. Interestingly, patients may not be aware of these body composition changes initially. Others have reported that "my body is changing," as early as four weeks after the start of HAART. The most precise way to assess these changes is through body composition studies. Bioelectrical impedance (BIA) is thought to be a good assessment tool for ambulatory settings
There are no reliable data establishing a true incidence or demonstrating which PIs may be more prone to causing the lipodystrophy syndrome. However, there is a suggestion that the syndrome may be more commonly seen with ritonavir and saquinavir, followed by indinavir, and then nelfinavir. There is little if any information on amprenavir.
In a complementary presentation, Krista Dong from Brown University described the lipodystrophy syndrome in women (abstract 12373), citing a self-reported incidence of 18% (21/116 patients). The average length of PI use was 13.6 months. Onset of changes was as early as six weeks after starting therapy. Ten women were taking indinavir, 10 were on nelfinavir or combination ritonavir/saquinavir and one was on ritonavir alone. Ninety percent of the women complained of increased abdominal fat, 71% complained of increased breast size and 62% complained of weight gain. Cholesterol levels were elevated in 48% and HDL levels were low in 86%. In eight women, serum was available prior to the initiation of PIs. There were clear increases in cholesterol and LDL levels after the initiation of HAART.
Cooper's group compared the genetic sequence of the HIV-1 protease to a number of gene banks to search for matches. They identified a 60 % to 70% homology between the active site of HIV protease inhibitors (between amino acids 19 to 30) and several key proteins that control lipid metabolism. These include LDL-receptor protein (LRP) at amino acid residues 2919-2930, cytoplasmic retinoic acid binding protein type 1 (CRABP1) at residues 116-127, and possibly CRABP2 which is located in skin cells. The CRABP1 is required for the transformation of retinoic acid to cis-9-retinoic acid and LRP assists in the movement of fats and binding of tissue pl asminogen activator. Cooper's group discusses these pathways in detail in the Lancet (June 20, 1998). The competitive inhibition of CRAPB-1 is hypothesised to be responsible for the peripheral fat wasting and the hyperlipidaemia. The inhibition of LRP's lipid binding capability exacerbates the hyperlipidaemia, which contributes to the central fat deposition, insulin resistance, and, in susceptible individuals, type 2 diabetes.
The hypothesis still requires testing and conflicting data need to be examined. Donald Kotler, for example, presented some very elegant data (abstract 32173) on over 100 patients with HIV infection not exposed to PIs that suggest that lipodystrophy is related to advancing HIV infection.
In the meantime, we should monitor the situation in our patients, Cooper said. He also made the point that first we also need to overcome our denial about the existence of this syndrome. Obviously this syndrome inspires an entirely new series of questions that need to be addressed in clinical settings. Some of the clinical issues requiring attention include the potential for reversibility of the syndrome, the advisability of changing drugs in the setting of this disease, and the treatment of some of the lipid disorders associated with the syndrome.
In symptomatic or advanced disease, the benefits of therapy outweigh the liabilities. The risk-benefit analysis of protease inhibitors, on the other hand, in asymptomatic patients is not known, according to Dr. Cooper.
While some individuals have begun to monitor the possibility of reversal of the syndrome if and when PI treatment is stopped, there is as yet no clear answer concerning this. Because this disorder may consist of more than one metabolic and clinical entity, it needs to be further defined before this question can be clearly answered.
Dr. Cooper indicated that the syndrome has not been associated with non-nucleoside drugs.
Another key point was the use of protease inhibitor-sparing regimens, a topic that has received considerable attention at this conference. While Cooper re-emphasised that he would not recommend changing a regimen that was showing immunological or virologic benefit, this strategy is an option for some. Finally, there were two poster presentations suggesting that recombinant human growth hormone (Serostim® ) can decrease the size and solidity of dorsocervical fat pads as well as redistribute truncal adiposity without the need to interrupt HAART. They had no impact on serum cholesterol or triglyceride levels (posters 32164 and 32182).
Antonio Carota (abstract 12375) presented data on the metabolic changes associated with the use of PIs. His group evaluated 131 patients on PIs and 25 patients on combination nucleosides. Significantly higher levels of uric acid, cholesterol, LDL, triglyc erides and ratio of total cholesterol:HDL (abnormal in 48% of the patients) were reported in the PI group. They described two cases of gout and 1 of diabetes mellitus believed to be related to PIs. Of note, they documented greater metabolic changes with ritonavir or ritonavir + saquinavir compared to indinavir alone. The incidence of lipodystrophy was 18% in their cohort.
Ravi Walli (abstract 41177) presented data on 67 patients taking PIs. Thirteen were treatment-naive patients and 18 were healthy controls. In this study, 61% of patients taking PIs had reduced insulin sensitivity and 50% of those had abnormal oral glucose tolerance tests.
Insulin resistance and emergence of diabetes mellitus are primarily attributable to hypertrigyceridaemia and alteration in lipid metabolism.
Dielman (abstract 12372) reported higher mean plasma concentrations of indinavir in 14 patients with urologic complications compared to 17 controls on indinavir without urologic complications. Zucman (abstract 12328) reported urologic complications in 21% (n=58) of persons taking indinavir. Despite measures to acidify urine and increase urine volume, two patients went on to develop nephrolithiasis. Nelson (abstract 12388) reported that 6.6% of 573 patients taking indinavir had loin pain. Ninety-five percent of these patients had microscopic haematuria.
Valerie Stone (abstract 12443) presented data on the self-reported reasons for stopping PI therapy in 256 patients from five clinical care sites in Rhode Island. Sixty-one percent of the patients took an average of 1.58 PIs (range 1-4). Sixty-two patients (39.7%) stopped one PI, 7.7% stopped two PIs, and 2.6% stopped more th an two PIs. The most common complaints were nausea/vomiting (40%), diarrhoea (40%), abdominal pain (30%), weakness (34%) and headaches (24%). In these self-reports, 18% discontinued because of drug failure, 19% because of poor adherence, 12% because of too many pills and only 2% did not know the reason why they stopped. Ferrer (abstract 12325) reported a discontinuation rate of 41.3% for 230 patients taking PIs. (The discontinuation rate for ritonavir was 60.5% versus 47.3% for saquinavir versus 33.3% for indinavir, p=0.006). It is interesting that lipodystrophy symptoms do not appear in this report.
Dube (abstract 32172) presented data on eight patients who stopped indinavir because of hyperglycaemia and changed to nelfinavir. Two patients improved with discontinuation of indinavir and did not have recurrence of hyperglycaemia when nelfinavir was ini tiated. Six patients switched directly to nelfinavir and had resolution of hyperglycaemia.
Reporters: Carl J. Fichtenbaum MD, Bill Valenti, MD
Source: Online Coverage from the 12 th World AIDS Conference, Medscape, Inc.
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More data on these observations are clearly needed to further define the extent and implication of lipid changes. Current data suggest a stronger association with ritonavir containing regimens but not yet to any convincing degree of statistical power. Options for those experiencing lipodystrophy or raised triglycerides include:
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OPPORTUNISTIC INFECTIONS
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Presentations at Geneva which were primarily concerned with CMV covered four main areas - effect of HAART on the pathogenesis of CMV, use of monitoring for predicting risk of CMV, use of new agents or changing practice with current agents and complication s which have occurred as a result of HAART.
The reduction of the incidence of CMV for people with access to HAART including PI's was shown in over a dozen reports, both in the reporting of fewer new cases and fewer relapses.
Analysis from the French Clinical Epidemiology Database also found that discontinuation of CMV maintenance therapy in patients with a CD4 count >=100 was found not to increase the risk of CMV recurrence [16/22239].
One study followed patients who stopped CMV maintenance therapy after a successful period of HAART and who had generated sufficient immune restoration to consistently test negative to CMV antigenaemia (CMV pp65) and blood cultures.
Of these 7 patients, 2 later developed low grade CMV antigenaemia with positive blood cultures (at 8 and 10 months) but these markers subsequently returned to negative within 4 weeks and remained so for the following 6 months. In these cases, transient low-grade rises of CMV viraemia did not indicate a recurrence of active CMV [32241].
Another study found a predictive value of CMV-antigenaemia (CMV-Ag) for CMV-retinitis. Of 51 patients tested, none of the 22 (43%) who tested negative went on to develop CMV over the 2 years of the study. 45% of those who tested positive went on to develop retinitis. In monitoring patients on treatment this test was not useful as a follow up marker for detecting risk of relapse [22251].
Several studies looked at the use of CMV plasma PCR testing to prioritise patients for CMV prophylaxis [44242, 22265] but found only moderate predictive sensitivity (only 53% of patients diagnosed with CMV tested PCR positive and only 42% of those showed positive results when blood stored three months prior to CMV diagnosis was re-tested).
The likely use of preventative intervention was the subject of a study screening for CMV among 794 HIV-infected patients at New York Hospital-Cornell Medical Centre. This results varied by risk group - haemophiliacs (42% seropositive), IVDU (80% seropositive), heterosexual intercourse (90% seropositive) and homosexual men (>98.5% seropositive) and produced higher general proportion of ser onegative (11%) than was expected. Given that the cost of providing CMV treatment for one person is higher than the total CMV screening costs for this whole study, baseline CMV tests together with educational support for avoiding future risks of CMV infection was recommended [42420].
Although HAART is resulting in many patients stopping maintenance therapy, there is still a pool of people who remain at risk from a relapse. Two studies looked at whether easier ganciclovir dosing regimens (once rather than twice daily induction and three rather than five times weekly for maintenance) could be as effective. Both these studies were small (n=12 and n=40). The induction trial lasted only 11 months and the maintenance trial was pre-HAART and both lead to the need for more detailed studies to be carried out [22267, 22254].
Another presentation looked at the safety of prolonging the dosing schedule of cidofovir from the normal 2-weekly schedule to once every three or four weeks. This study, in which 8 out of 10 patien ts elected to extend the dosing period, primarily to reduce the risk of cidofovir associated side effects resulted in no cases of reactivation, although some of the patients had CD4 counts >= 100 (range 20 to 399) and therefore could be expected not to relapse even if they stopped therapy altogether [32239]
The high prevalence of CMV drug resistance remains a real problem for patients who have to continue treatment. A US study of 122 patients with CMV retinitis found life table analysis of developing a resistant virus for each drug at 0, 3, 6 and 9 months was: ganciclovir - 3%, 7%, 12% and 27%; foscarnet - 3%, 9%, 26% and 37%; cidofovir - 7%, 29%, 29% and 29% respectively [32233].
The incidence of ganciclovir resistance following intra-ocular implants was found to be 8% in patients who had previously received subtherapeutic levels of systemic treatment [32235].
High level ganciclovir resistance from long-term use makes the use of cidofovir as a salvage therapy unlikely [60659] and a possible option to retain sight in these patients could come form the newly approved anti-sense oligonucleotide fomivirsen (ISIS 2922).
Safety data pooled from four randomised control studies and two non-controlled studies compared low (3mg/ml) and high (6.6mg/ml) doses of fomivirsen in 319 patients, many of whom have failed other CMV treatments. The lower dose produced fewer adverse even ts: transient elevated intra-ocular pressure (10% vs 18%), vitritis (3% vs 12%) renal detachment (3% vs 10%) and mild-moderate anterior chamber inflammation (9% vs 16%) [22245].
While flare-ups of newly presenting and relapsing OI's like CMV and also hepatitis B [22239, 60323] are known, an unexpected complication from otherwise successful HAART is the increased reporting of non-CMV related loss of vision in a significant number of people who previously had active CMV retinitis. The immune recovery can cause an intraocular inflammation affecting especially the retina (cystoid macula oedema) and vitreous jelly (vitritis) [22240].
These effects only occur in eyes that have previously been diagnosed with retinitis and incidence has tended to be higher in people with higher CD4 counts although this difference was not statistically significant.
The oral presentation covering this area disappointingly suggested that the reintroduction of CMV maintenance treatment when close monitoring showed an increase of these symptoms may be necessary to limit permanent damage.
Although the use of steroids increases the potential risk of CMV reactivation they have been used successfully to hold back incidence and severity of vitritis.
Author: Simon Collins, ATP.
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OTHER NEWS
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Following the interruption in supply of ritonavir capsules (NorvirTM) due to unexpected manufacturing difficulties (see Doctor Fax issue 51) AIDS Treatment Project has become aware of confusion over the storage requirements of the replacement liquid formulation. Existing stock of capsules is unaffected and safe for use.
The liquid formulation currently being dispensed is identical to the ritonavir liquid previously available alongside ritonavir capsules. However, instructions concerning storage requirements have been amended. It was previously instructed that ritonavir liquid should be stored under refrigeration as a safety consideration to extend shelf-life. These instructions have now been replaced by updated recommendations NOT to refrigerate ritonavir liquid. Bottles are being re-labelled with this new instruction but some product may still exist in pharmacies with the older requirement for refrigeration on the label.
Ritonavir oral solution should NOT be refrigerated and should be stored at room temperature (between 20o - 25o) and used within 30 days of dispensing. It is important to shake the solution well before use. If, after shaking, particles or precipitate can be seen in the solution, take the next dose and then return the remaining liquid to the pharmacist for a fresh supply. Shaking the bottle vigorously is usually sufficient to dissolve the precipitate back into the liquid.
It is understood from U.S. sources that the thirty days shelf-life is considered to be AFTER opening the bottle, and that unopened, unrefrigerated shelf-life is indicated by the product use by expiration date.
Refrigeration of ritonavir liquid is more likely to cause crystallisation or precipitation, storage at room temperature is a precautionary measure to minimise the possibility of crystallisation occurring in the liquid. At this time no crystals have been observed in ritonavir liquid stored correctly at room temperature.
Children are the main consumers of ritonavir liquid and a few tricks have been developed to stop them gagging on or spitting out the noxious tasting liquid. Now we are sure if kids can get it down, and keep it down...
The principle here is to overpower the taste buds with a flavour and coat them so that the taste of ritonavir is minimised. Mixing the ritonavir however with anything, ice cream etc. does not work on children as the ritonavir can overpower the other flavours. This is not the same as getting the taste buds to already be overpowered by some flavour and THEN taking the ritonavir.
Try using a straw to suck the liquid straight to the back of your throat having first mixed the ritonavir with a flavoured milk. Some centres are also advising using dosing syringes to squirt the liquid directly to the back of the throat, so bypassing the taste buds.
Possibly for those who still cannot tolerate the taste, local anaesthetic topical products such as chloraseptic (Strepsils TM) might be used first to numb the taste buds.
Source: Adapted from " Search for a Cure"
Abstract
OBJECTIVE: To evaluate the efficacy of melaleuca oral solution in AIDS patients with fluconazole-resistant oropharyngeal candida infections.
DESIGN: A prospective, single centre, open-labelled study.
SETTING: A university-based inner-city HIV/AIDS clinic.
PATIENTS: Thirteen patients with AIDS and oral candidiasis documented to be clinically refractory to fluconazole, as defined by failure to respond to a minimum of 14 days of > or = 400 mg fluconazole per day. Additionally, patients had in vitro resistance to fluconazole, defined by minimal inhibitory concentrations of > or = 20 microg/ml.
INTERVENTIONS : Patients were given 15 ml melaleuca oral solution four times daily to swish and expel for 2-4 weeks.
MAIN OUTCOME MEASURES : Resolution of clinical lesions of oral pseudomembranous candidiasis lesions. Evaluations were performed weekly for 4 weeks and at the end of therapy for clinical signs of oral candidiasis. Quantitative yeast cultures were performed at each evaluation.
RESULTS : A total of 13 patients were entered into the study, 12 were evaluable. At the 2-week evaluation, seven out of 12 patients had improved, none were cured, and six were unchanged. At the 4-week evaluation, eight out of 12 patients showed a response (two cured, six improved), four were non-responders, and one had deteriorated. A mycological response was seen in seven out of 12 patients. A follow-up evaluation 2-4 weeks after therapy was discontinued revealed that there were no clinical relapses in the two patients who were cured.
CONCLUSIONS: Melaleuca oral solution appears to be effective as an alternative regimen for AIDS patients with oropharyngeal candidiasis refractory to fluconazole.
Ref: Efficacy of melaleuca oral solution for the treatment of fluconazole refractory oral candidiasis in AIDS patients. Jandourek A, Vaishampayan JK, Vazquez JA. AIDS 1998 Jun 18;12(9):1033-1037
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