Medical Consultant
12 th World AIDS Conference28 June - 3 July 1998, Geneva, Switzerland
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28 June - 3 July 1998, Geneva, Switzerland |
Upwards of 12,000 delegates attended the 12th World AIDS Conference, the major international conference which takes place every two years. In addition to basic and clinical science (which ATP exclusively reports), the World AIDS conference also has numerous presentations on epidemiology, prevention, public health and social science. As with this years Retrovirus conference a steady infiltration of both laboratory and clinic based immunological studies was evident. Continued concern over the long-term tolerability and durability of current combination antiretrovirals manifests as a desire to understand host-based mechanisms of virological control.
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ANTIRETROVIRALS |
Efavirenz (SUSTIVA(TM), DMP-266), an NNRTI, in combination with zidovudine and lamivudine compared to indinavir/zidovudine/3TC at 24 weeks
The big antiretroviral story of day 1 at the Geneva Meeting was the first report of the pivotal efavirenz trial (DMP 266-06) presented by Schlomo Staszewski. Many practitioners have experience with this agent as part of salvage therapy, but little data in naï ve patients has been presented. Today we had our first glimpse of the activity of efavirenz as part of a 2- and 3-drug combination therapy in comparison to a standard 3-drug regimen. This study put an NNRTI, efavirenz (EFV), head-to-head with indinavir in an attempt to clearly establish a 3-drug combination including an NNRTI as a combination with comparable activity to 3-drugs including a protease inhibitor.
The study included 450 patients who were naïve to 3TC, NNRTIs, and protease inhibitors, and had viral loads > 10,000 copies/mL and CD4+ counts > 50 cells/mm 3. Pre-treatment viral loads were about 70,000 copies/mL for the entire group and CD4+ counts were 345 cells/mm 3. Patients were randomised to one of three open-label treatment arms:
Indinavir was dosed as 800 mg q8H as part of the 3-drug combinations, but was given as 1000 mg q8H when used with EFV as part of the 2-drug combination because EFV decreases serum concentrations of IDV. Data up to study week 24 were presented.
Viral load reductions of -2 logs or more were seen with each group. Reductions of viral load below 400 and 50 copies/mL were analysed by two intent-to-treat analyses and by an on-treatment analysis (counting only those patients still being followed on assigned medication). In the most stringent intent-to-treat approach, patients who dropped out of the study for any reason were considered as treatment failures (i.e., viral loads not less than 400 or 50 copies/mL). In the second intent-to-treat analysis, the last observation of the patient was carried forward (LOCF) and considered as the data point for week 24 analysis.
At week 24, 95% of patients on ZDV + 3TC + EFV, 87% of EFV + IDV recipients, and 89% of ZDV + 3TC + IDV recipients had a viral load < 400 copies in the on-treatment analysis. Using the most stringent criteria (drop-out = failure), 75% of patients assigned ZDV + 3TC + EFV had viral load < 400 copies/mL, compared to 63% of those assigned to EFV + IDV, and 56% of those assigned to ZDV + 3TC + IDV. The differences between ZDV + 3TC + EFV and ZDV + 3TC + IDV were statistically significant (p < 0.05).
Some of the differences seen with the intent-to-treat analysis can be explained by the higher dropout rate among patients on indinavir. Adverse events leading to treatment discontinuation occurred in 26/1 48 (18%) of patients on ZDV + 3TC + IDV, compared to 7/148 (5%) patients on EFV + IDV, and 10/154 (6%) patients on ZDV + 3TC + EFV. Commonly reported grade 2 (moderate) or more severe adverse events included nausea and vomiting which were most common in patients on ZDV + 3TC + IDV, rash occurring in approximately 12% of EFV recipients, and the central nervous system symptoms of headache and dizziness reported in about 5% and 7% of EFV recipients, respectively.
The most impressive testimony to efavirenz's a ctivity was presented in a subanalysis of 117 patients with baseline viral loads > 100,000 copies/mL. In an on-treatment analysis, a remarkable 90% of these patients had viral loads < 400 copies/mL after 24 weeks of therapy, compared to 78% of patients on the 2-drug EFV + IDV combination, and 73% of ZDV + 3TC + IDV recipients.
This study creates a clear protease-sparing option for initial therapy. The results are still somewhat limited by the short duration of follow-up. Clearly, durable suppression of viral replication is the goal of therapy and a more prolonged follow-up period may alter the outcomes to some extent. Studies with nevirapine and delavirdine as part of triple combinations demonstrated that patients were most likely to have viral loads below the limit of quantification after 24 weeks of therapy, with a higher failure rate developing over time. Fewer mutations are required for virus to become resistant to the NNRTIs compared to the protease inhibitors, so more failures over the next 24 weeks may be seen in the EFV arms. However, many studies have shown that the surest way to prevent resistance is to reduce viral loads to the lowest possible levels, and efavirenz clearly passes that test. A possible point of contention for study-design purists is that the study was not placebo controlled. This may have biased the reporting of adverse experiences because patients may have been familiar with the possible toxicity's associated with each agent.
Ref: Poster Session 22336:
Coverage by Ian Frank, M.D.
Source: http://http://www.thebody.com
This study compared the triple combination of AZT/3TC/efavirenz with the double combo of AZT/3TC in naïve patients. Early in the study, it be came clear from new research that AZT/3TC was not adequate, and patients who had started on the double combo changed nucleosides to ddI and d4T and added both efavirenz and indinavir. It was a double blind, placebo-controlled study of 137 patients, and there were initially 3 efavirenz doses (200 mg or 400 mg or 600 mg). Mean HIV RNA 4.7 +/- 0.5 log10 copies/mL, mean CD4 count 370 +/- 194 cells/mm 3 . Using the optimistic (and widely used) as treated analysis (only looking at those still taking their treatment), 100% of those on efavirenz 600 mg (now the recommended dose) were below 400 copies at 24 weeks and 36 weeks. 80 to 95% of those who started at suboptimal doses were below 400 copies at 24 weeks and 36 weeks. Of those who started on AZT/3TC and intensified, 65 to 70% were below 400 at week 24 but it appeared to be dropping after that. Using the stricter intent to treat analysis, 80% of those in the three efavirenz containing arms were less than 400 copies. CD4 increases were between 100 and 150 cells at 36 weeks and still increasing. As with all efavirenz studies, some patients experienced sleepiness, insomnia, difficulty concentrating or euphoria, but in most cases it cleared up and was tolerable. This study complements the 006 study in showing that 2 nukes and efavirenz is an excellent "protease sparing" regimen in drug naï ve patients, at least over 24 to 36 weeks. It is reassuring that during the dose ranging studies, people who received lower doses of efavirenz with the nucleosides did not have early resistance.
Ref: Poster Session 22334
Presented by David Haas,
Source: http://http://www.thebody.com
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The DMP 266-06 trial provides compelling early data for the effectiveness of an NNRTI based triple combination, especially as the response in those with VL >100,000 was similar to that seen in those with lower starting VL's. More dropouts, indeed, more than seen in similar studies occurred in the IND arm - mostly for initial G-I toxicity. This biases the intention to treat analysis in favour of EFV (but may - some would argu e , represent 'real-life' outside of a research setting). It should also be noted that IDV was dosed tid and that 200mg capsules of IND were used. Pill volume and frequency were therefore higher in the IND arms. As the study was open-label patients knew the other arm were getting BID dosing and 9 capsules less per day.
Data on NNRTI's needed to reassure of equivalency to PI's include issues of immune function (does the immune system recover qualitatively on NNRTI's as has been seen with PI's?). Is immune rest oration as rapid and will lymph node clearance be seen? Additionally, long-term toxicity data is needed; PI's were assumed to be safe and relatively non-toxic at a similar stage in the game. Will we be looking for NNRTI-sparing regimens in 3 years time due to unforeseen longer-term toxicities? |
Martin Fisher of the Royal Sussex County Hospital, Brighton presented data on 502 patients taking part in the named-patient programme for the provision of nevirapine (NVP) prior to licensing in Europe. Retrospective case note review was used to obtain information on prior antiretroviral treatment, virologic and CD4+ lymphocyte response and reported toxicity.
141 subjects were antiretroviral naïve with median baseline VL and CD4 count of 4.84 log (range, 2.60 to 6.48) and 217 cells/mL (range, 0 to 1209) respectively when prescribed a NVP containing regimen. Choice of concomitant nucleoside analogues (NA's) was:
| d4T + ddI | 61 subjects |
| ZDV + ddI | 46 subjects |
| ZDV + 3TC | 16 subjects |
| d4T +3TC | 11 subjects |
| ZDV + ddC | 6 subjects |
| ddC + 3TC | 1 subject |
Six-month data showed approximately 75% of naïve patients achieved VL less than 400 copies/mL. Median change in CD4+ lymphocytes at six-months was approximately 100 cells/mL (both results intent to treat analysis).
361 subjects were antiretroviral experienced (median 15 months experience), of these, 124 were also protease inhibitor experienced. Baseline median VL and CD4 count for these experienced patients was 4.45 log (range, 2.59 to 6.89) and 200 cells/mm 3 (range, 0 to 783) respectively. Choice of concomitant antiretrovirals was:
| 2 NA's | 247 subjects |
| 1 NA + 1 PI | 42 subjects |
| 2 NA's + 1 PI | 28 subjects |
| 2 PI's | 18 subjects |
| 3 NA's | 12 subjects |
| 1 NA + 2 PI's | 8 subjects |
| Other | 6 subjects |
In addition to being naïve to any NNRTI, 5 patients were able to initiate 3 new antiretrovirals concomitantly, 124 initiated 2, 99 commenced one, and 133 did not have a choice of antiretrovirals to which they had not been previously exposed.
Six-month data in the experienced patients showed approximately 40% achieving a viral load reduction to less than 400 copies/mL and a median CD4 rise of approximately 42 cells/mm 3 (both results intent to treat analysis). Sadly, results were not available for VL assay of <50 copies/mL.
Factors associated with achieving a VL <400 copies/mL at 6 months were being antiretroviral naïve vs experienced (p=<0.005) and commencing new antiretrovirals concomitantly (0 vs 1 vs SYMBOL 179 "Symbol" 10 2, p=<0.025).
7.2% (36/502) of all patients experienced toxicity attributed to nevirapine severe enough to require discontinuation including 22 cases of rash (2 of which were Stevens Johnson Syndrome).
Ref: Poster Session 32248
Reported by Paul Blanchard
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Efavirenz is not tolerated by all due to it's potential for disabling CNS side-effects. Nevirapine or delavirdine represent additional NNRTI choices for those intolerant to efavirenz. The further data on these two compounds presented at Geneva give additional support to their utility and suggest that in appropriate regimens and patient populations they can provide potent antiretroviral effects. Head to head comparisons are now needed amongst all agents currently available in this class to establish if there are difference responses in varied target populations, potency and durability. |
Although "protease sparing" is the current rationale for use of an NNRTI in a triple combination regimen there is no logical reason why the reverse sequence should not be as effective (NNRTI sequenced AFTER PI-regimen based failure). A study by Pell and colleagues of Sydney, Australia used retrospective case note based review to identify 39 patients with prior PI experience who were subsequently prescribed nevirapine (NVP) + d4T + ddI.
Mean duration of prior PI-based therapy was 57 weeks (range, 17-134). Only 4 of the 39 patients were naïve to all 3 drugs (NVP, d4T and ddI) 79% had taken d4T before, 31% had taken ddI before and 4 patients (10%) had previously taken NVP. It should be noted that virologic failure was not the only reason for discontinuation of prior PI-based therapy - reasons cited were:
| elevated VL | 20 patients |
| diarrhoea | 6 patients |
| convenience | 5 patients |
| lipodystrophy | 3 patients |
| nausea | 2 patients |
| non-adherence | 2 patients |
| LFT elevations | 1 patient |
Of 15 patients who switched from their PI-based to this NVP-based regimen while having a VL <400 copies/mL, 11 remained <400 through 26 weeks. The other 4 patients had a rise in VL to >400 copies at 8, 10, 11 and 18 weeks. Of 24 patients who had a VL >400 while on their PI-based combination (mean 5.28 log, range 3.13 to 6.47), 13 (54%) achieved <400 copies during the 26 weeks of follow-up. Of these, 6 patients had never previously achieved a VL of <400 copies/mL. Mean baseline CD4 count was 367 cells/mm 3 (range, 71-997) with 29 patients out to 26 weeks experiencing a mean change of +74 cells.
The combination was generally well tolerated with 9 patients discontinuing due to toxicity (5 for elevated LFT's, 2 for anorexia/nausea and 2 for peripheral neuropathy).
The authors concluded that for patients experiencing difficulties with protease inhibitors, changing to a more convenient NNRTI-based combination is an attractive strategy, tentatively supported by this study but requiring further investigation in controlled trials.
Ref: Poster Session 22357
Reported by Paul Blanchard
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The rational not to spare NNRTI's - but to use them 1 st line is that, at least for DLV and NVP, activity may be attenuated by presence of NA related genotypic change (primarily ZDV resistance). The study outlines above does, however, underline that these agents may make a contribution to salvage activity. Maintaining some NA options also appears crucial to s uccess in salvage (see data from SPICE [DocFax 50] and the open-label NVP data from Martin Fisher outlined below). |
Delavirdine (DLV) is the third NNRTI currently available in Europe. Michael Para of Columbus, Ohio presented an interim analysis of viral load and CD4 lymphocyte response in a blinded, randomised study of the triple combination DLV+ZDV+3TC vs the double combinations of ZDV/3TC or ZDV/DLV. Patients were not exclusively na ïve, but were limited to prior experience of a maximum of six-months of ZDV (all were naïve to 3TC and DLV).
Approximately 123 patients were assigned to each treatment arm with baseline demographics being similar across the groups. Mean baseline viral load and CD4 counts ranged from 22,000 -31,000 copies/mL and 354-360 cells/mm 3 respectively. Dosages of each drug used were DLV 400mg tid, ZDV 200mg tid, 3TC 150mg bd (once daily if subject was less than 50 kg). Viral load response was measured both with a standard as say (cut-off 400 copies/mL) and the Ultrasensitive assay (cut-off 40 copies/mL). This report will concentrate on the results of the triple therapy arm (DLV/ZDV/3TC), the other two arms being substandard. Suffice it to say that the 3-drug arm performed significantly better in VL response than either 2-drug arm at all time points. The DLV/ZDV arm showed the worst performance of all three arms in both VL and CD4 response.
52 week data for the patients receiving DLV/ZDV/3TC showed 68% with a viral load below 400 copies/mL and 59% below 40 copies/mL. CD4 response at this time-point showed a mean change from baseline of approximately +80 cells/mm 3 . It should be noted that of the initial 122 patients in this study arm only 34 were included in the 52 week analysis. The analysis presented was one of 'on therapy'.
An additional analysis was performed of time to virologic failure (from date of 1 st study dose to 1st failure event - from below assay to above assay, or clinical progression if earlier). Patients who never a chieved VL below quantification of the assay were considered as failures at day 1. This analysis revealed that at 52 weeks the regimen had failed approximately 60% of patients in the triple therapy arm (if <400 copies/mL criteria were used) and 70% of patients if the stricter criteria of <40 copies were applied. This time to failure was significantly longer than seen with both 2-drug arms.
Approximately 32% of patients in each of the two DLV-containing arms experienced rash as compared to 15% in the ZDV+3TC arm; 11% of the rashes were severe. 3% of all patients had to discontinue treatment due to rash.
Ref: Poster Session 129/12219
Reported by Paul Blanchard
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Time to virological failure is likely to be the most stringent analysis (even more so than intent to treat). In this study this form of analysis was requested by the FDA and is likely to become the new gold-standard for regulatory submissions. In all the results here appear similar to the INCAS study (of nevirapine/ZDV/ddI) remembering that 20% of subj ects in this study were not treatment naï ve. Delavirdine has the advantage (for some combinations) of being an inhibitor of cytochrome p-450 CYP3A whereas both nevirapine and efavirenz are inducers of this enzyme. Combinations of DLV with some PI's can yiel d advantages in boosting and "smoothing out" PI pharmacokinetics |
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NNRTI's and Protease Inhibitors used together
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This sma ll open label study from Brown University is interesting because it is one of several "triple class" studies, that combine a protease inhibitor with one nucleoside (d4T) and one non nucleoside (NNRTI, in this case nevirapine). The study was primarily designed to look at the pharmacological interaction. D4T and nelfinavir (three time a day dosing) were given for 7 days, drug levels were measured over an 8 hour interval, then nevirapine was added and drug levels were again measured. Twenty-five patients started the study; 20 have been on the regimen for 30 to 50 weeks. Half were drug experienced with past AZT, d4T, ddI or 3TC. Median viral load was 4.5 log (30,000 copies) and median CD4 count was 280. The antiviral efficacy so far has been impressive, with at least 85% (intention to treat) below 400 copies/mL and 50% below 50 copies. This suggests that triple class regimens are quite potent. We should keep in mind the small size of the study, though, and the concern about what would be left to use after this regimen. Whether triple class regimens are better than protease plus NNRTI combinations (such as efavirenz indinavir or nevirapine nelfinavir) must be determined by head to head comparisons with long term follow-up.
Ref: Poster Session 12275
Coverage by Andrew T. Pavia, M.D.
Source: http://http://www.thebody.com
Lyle and colleagues performed a retrospective chart review to examine the response to this double PI + NNRTI combination. 25 patients were identified of whom 24 had been extensively pre-treated with nucleoside analogues. 18 had also been treated with at least one protease inhibitor. Mean baseline viral load and CD4 count for these patients was 4.25 lo g and 239 cells/mm 3 respectively. The majority of patients combined d4T and 3TC with the DLV/IND/NFV.
Results revealed that 20% of patients had a viral load <400 copies at baseline. This percentage rose to 52 % at one month and was maintained at 50% at both 3 and 6 months. Ultrasensitive VL assay (<40 copies/mL) showed that 32% (7/22) were <40 copies at 3 months and 65% (13/20) were <40 copies at six months. CD4+ count was a mean of 55 cells above baseline at 6 months. Three of the 25 patients had to discontinue therapy because of adverse events (diarrhoea, GI disturbance, and weakness).
The authors concluded that this combination of antiretrovirals from 3 different classes (including "recycled" NA's) could have some success in heavily pre-treated patients. Most had used 2 or even 3 PI's and all approved NA's and NNRTI's before starting the regimen used in this study. Of particular note is the further mean reduction in HIV RNA from month 3 to 6, showing a sustained benefit. It should also be noted that one patient stopped IDV prior to reaching 6 months, but his HIV RNA remained below 40 copies/mL, two patients switched from IDV to SQV-sgc. The one treatment naï ve patient had a baseline VL of >1 million copies/mL and a baseline CD4+ cell count of 17 cells/mm 3. However, he still managed to achieve a VL of <40 copies/mL at 2, 3 and 6 months, CD4 count also increased to 186 cells at 6 months. This patient was receiving d4T/3TC in addition to the DLV/IND/NFV.
Ref: Poster Session 12329
Reported by: Paul Blanchard
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Clearly there is interest in using all available drug classes in salvage, but many physicians remain wary of using all drug classes up-front - potentially leaving no options for salvage. A further concern, even with salvage, are the pharmacokinetic interactions between increasingly common double PI + NNRTI combinations. Data on 3-way drug interactions amongst representatives of these classes are urgently required and both patients and physicians using such regimens must weigh carefully the potential risks as well as benefits. |
http://http://http://www.healthcg.com/hiv/scripts/12thAIDS/dailysummary.cfm?day=12th+Day+2
Ref: Abstract 125/12203
Author: Joseph Eron, M.D.
Source: http://http://www.healthcg.com
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More data are needed on the EFV-NFV interaction as conflicting data currently exist. This combination does, however, represent another salvage option. |
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ANTIRETROVIRALS IN PREGNANCY
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Karen Beckerman presented the experience at the Bay Area Perinatal AIDS Center at San Francisco General. They have a multidisciplinary comprehensive program for HIV-infected pregnant women. Since 1996, an increasing proportion of the mothers chose double or triple combination therapy. In the most recent group, more than 80% have chosen protease-containing therapy. Most mothers had undetectable viral loads at delivery with this approach. Of the last 61 pregnant women, 60 have had uninfected babies. The mother who transmitted was not on medication during the third trimester. Side effects were those typically encountered with the drugs, and no unexpected adverse outcomes have been seen in the babies. This is extremely good news. Although it is not a controlled study, it suggests that more potent therapies may drive the transmission rate from mother to child from the 8% seen with AZT monotherapy in ACTG 076 to closer to 1 or 2%, while providing women with the state of the art antiviral therapy. This may come from lowering cell-associated virus and perhaps lowering virus in other compartments.
It is important to keep looking very hard at the safety of these drugs in pregnancy, although we should not deny them to women just because the studies are not in yet. However, there may be surprises. It is likely that all drugs are not equally safe. Efavirenz is the only one to clearly cause birth defects in monkeys, and women who are or want to become pregnant should choose other drugs [ Ed: Efavirenz was the ONLY drug to be tested in a monkey model. This does not imply that the others are safer!]. An observational study from the Geneva group raised some concerns
Ref: Session 459/12151:
Coverage provided by Andrew T. Pavia, M.D.
Source: http://http://www.thebody.com
This group reported on 37 consecutive pregnant women treated with triple combination therapy. Since they defined an adverse event as any abnormal lab value, it was not surprising that lab adverse events were common in mothers, but mostly consisted of abnormal liver function tests, abnormal bilirubin, and some anaemia, all quite common in any group of patients on AZT, indinavir, or ritonavir. Two women had kidney stones on indinavir. One woman had an ectopic pregnancy; she was taking hydroxyurea when she became pregnant. 30 babies have been delivered so far. 8 were anaemic, a minor complication often seen in the first 6 weeks when the baby is on AZT. One third of the babies were born prematurely, although most apparently were not significantly premature. Two babies whose mothers were on indinavir had intracerebral haemorrhages. One was of these was premature, where this is a common complication but the other was born at term. One baby, also exposed to indinavir had biliaryatresia, a rare birth defect. Their conclusion, and I suppose mine as well, was that the complications in the mother were what one would expect on treatment. Three unexpected events were seen in 30 children, but there is no way of knowing whether these were related to the drugs unless more cases appear and a comparison can be made with an HIV-infected group not on therapy. However, we clearly need to keep watching, and sharing the information as it becomes available. I have tended to recommend nelfinavir in pregnancy because of timing of meals, worry about kidney stones in mothers and not knowing if the elevated bilirubin in adults might mean some liver toxicity for a foetus, but it is mostly instinct until we have trials.
Ref: Poster Session 32453:
Coverage provided by Andrew T. Pavia, M.D.
Source: http://http://www.thebody.com
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Without a control group it is unclear if these observed complications were additional to those seen in HIV-infected mothers who in this cohort may also have been enrolled in methadone maintenance programmes. What does appear clear is the high success rate of triple therapy at reducing perinatal transmission. The dilemma exists that if women are to receive appropriate antiretroviral treatment during pregnancy unforeseen adverse events may emerge . Prematurity and birth defects are of great concern, however, inadequate therapy for the mother to be (with resistance risks) and transmission of HIV to the unborn child are also significant risks. Therapy decisions must be made on an individual basis bet ween informed patients and specialist physicians. As this issue of the Doctor Fax was being compiled, news was released from the U.S based Perinatal Research Agenda Committee that due to concerns over the data from Geneva, enrolment into 4 ongoing trials involving protease inhibitors in pregnant women has been suspended. Dr Gwen Scott, Co-Chair in a letter to principal investigators explained that " Although events were not observed in all of the studies, the PACTG Perinatal RAC and the protocol teams along with the DAIDS decided that the balanced approach to this issue would be for all enrolment into the trials to be "on hold" until these cases have been fully evaluated and an explanation for the premature deliveries is defined. An enrolled study of SQV-sgc/ZDV/3TC begun in the second or third trimester of pregnancy is currently ongoing at the Chelsea and Westminster Hospital, London. |
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OTHER NEWS
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The British HIV-1 Association (BHIVA) recently released revised guidelines for the treatment of HIV-seropositive patients with antiretroviral drugs. The goal of antiretroviral therapy should be to develop an initial regimen that achieves the best virological responses but allows for possible benefits from future therapy if needed. Even though U.S. guidelines recommend that treatment begins when viral load is either detectable or above 10,000 copies/mL regardless of CD4 cell count, BHIVA continues to suggest that treatment should be individualised and begun prior to irreversible damage of the immune system. Even so, the therapy should reflect risk management and strike a balance between the potential benefits of delaying therapy and the risks associated with a multidrug therapy that lasts throughout life. For patients with less than 50,000 RNA copies/mL, therapy should begin with two nucleoside analogues plus a non-nucleoside reverse-transcriptase inhibitor (NNRTI) or a protease inhibitor. Patients with more than 50,000 RNA copies/mL should initially be given two nucleoside analogues plus one or two protease inhibitors. Even though using two nucleosides and an NNRTI could be more beneficial because it leaves open the opportunity to protease inhibitors later, studies suggest that patients with viral loads above 50,000 copies/mL should begin with protease-inhibitor-containing therapies. BHIVA no longer recommends the initial use of two nucleoside analogues except in unusual circumstances. The primary determinant of treatment failure should continue to be the measurement of viral load, which should be less than 500 copies/mL by 24 weeks of therapy in treatment-naive patients.
Ref: Lancet (25/07/98) Vol. 352, No. 9124, P. 314; Gazzard, Brian; Moyle, Graeme; Anderson, J.; et al.
Source: CDC Daily News Summaries.
The U.K. division of Pharmacia & Upjohn would like to make it clear that the company is committed to a future role in the field of HIV therapeutics. This statement by the company follows speculation by U.S. treatment specialists that P&U were planning to withdraw from the field of HIV (see DocFax issue 48). Graeme Robertson, product manager for P&U's HIV drugs in the UK states that "we are continuing to seek regulatory approval for delavirdine in Europe and are aggressively pursuing development of tipranavir (a non-peptidic protease inhibitor) and PNU 142,721 (a second generation NNRTI)."
Issue 50 of AIDS Treatment Projects Doctor Fax contained an article entitled "Rapidly achieving less than 50 copies/mL of plasma HIV-RNA may be vital to long term success of combination antiretroviral therapy". The comment box following this article incorrectly referred to NucleoSIDE analogues as being active in their native orally administered form. This statement should have been applied to nucleoTIDE analogues. Conversely, the statement that nucleoTIDE analogues required phosphorylation to their active form should have referred to nucleoSIDE analogues.
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ISSUE 52 of AIDS Treatment Projects Doctor Fax will report on further data from Geneva on double protease inhibitor based combinations, novel dosing strategies and updated information on the lipodystrophy syndrome. |
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TREATMENT ALERT
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The active ingredients in Norvir liquid and Norvir capsules are identical, as is their activity against HIV. Changing to Norvir liquid should not affect your anti-retroviral regimen.
Each Norvir capsule contains 100 mg of active drug, and each mL of Norvir liquid contains 80 mg of active drug. For your convenience, Norvir liquid comes with a dosing cup that provides markings indicating the amount of liquid to be taken for the two most common doses. It is important to measure the correct dose of Norvir; therefore, the dosing cup has been specially designed to provide the right dose of Norvir liquid. This cup should be used to measure a dose. Please be advised that when measuring a dose, the cup should be placed on a flat surface at eye level, and the cup filled with Norvir liquid to the line showing the appropriate dose. You should wash the dosing cup with soap and warm water as soon as possible. The dosing cup is not dishwasher safe .
Patients may improve the taste of Norvir liquid by mixing with chocolate milk or other flavoured dietary supplement drinks.
To ensure continued stability of Norvir liquid, it should not be refrigerated and should be stored at room temperature (below 25oC/77o F) and used within 30 days of dispensing. It is important that you shake the liquid well before each use. Your health care providers have been informed of the dosing and handling for Norvir liquid.
People will receive Norvir liquid when their pharmacy runs out of Norvir capsules. After finishing your prescription for Norvir capsules, you should begin taking Norvir liquid at your next scheduled dose. It is critical for you to take your medication at the prescribed dose and time recommended by your physician. If you have questions about the liquid, contact your physician immediately.
We deeply regret this inconvenience and appreciate your understanding and patience as we work to solve the problem. Abbott is committed to doing everything it can to allow patients to continue Norvir therapy without interruption, and to resuming timely delivery of Norvir capsules.
Pharmacists and physicians are being informed of dosing instructions to address the capsule-to-liquid conversion.
Abbott has contacted and is working with the U.S. Food and Drug Administration (FDA), the European Agency for the Evaluation of Medicinal Products (EMEA) and other international regulatory agencies to address the problem. Abbott will be communicating with health care providers, consumers and the AIDS community through letters.
As a result of the current difficulties, until the capsule inventory is depleted, Abbott UK plan to fill orders according to customers historical ordering patterns.
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If you have questions or concerns, please ask your doctor or call Abbott at 0800 0183 340 (UK freephone enquiry line -24hr). |
| 6 ritonavir capsules (100mg each) | 7.5 mL of ritonavir liquid |
| 5 ritonavir capsules (100mg each) | 6.25 mL of ritonavir liquid |
| 4 ritonavir capsules (100 mg each) | 5 mL of ritonavir liquid |
| 3 ritonavir capsules (100 mg each) | 3.75 mL of ritonavir liquid |
| 2 ritonavir capsules (100 mg each) | 2.5 mL of ritonavir liquid |
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Due to wide variance in teaspoon sizes ATP recommends you request an appropriately sized syringe from your pharmacist to ensure accurate measurement of the liquid formulation. Liquid Norvir should not be mixed with water as this may cause precipitation of solids. This does not affect drinking liquids (including water) either side of the dose. Sucking an ice-cube just before dosing, mints and salty foods may also help reduce the unpleasant taste of the liquid. Norvir liquid contains a higher proportion of alcohol than the capsule formulation and should be used with caution in those on metronidazole, tinidozole and antabuse - particularly if liver function is abnormal. |