DOCTOR FAX

ISSUE 12 27th November 1996

Sourced Compiled and Edited by Paul Blanchard
Medical Advisor - Dr Graeme Moyle, Chelsea & Westminster Hospital.

Contents

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ANTIVIRALS




Indinavir Launched in UK Amid Shortage Reports



Merck's protease inhibitor, indinavir sulphate (Crixivan) has been launched in the UK amid concerns that the company may be unable to supply enough drug to meet worldwide demand. The price has been set at 9.64 ECU per day ($12).

Reports suggest that in Belgium, Italy, Spain, Portugal and the UK, not all HIV-infected patients who could benefit from protease inhibitors are receiving them. In the UK, The Terrence Higgins Trust says that most specialist HIV clinics are making sure patients receive these drugs, even if it means that they go over budget. However, problems may be occurring for patients treated by GPs or at non-specialist clinics. The UK AIDS Treatment Project estimates that almost 12,000 deaths could be prevented in these countries during 1997 if protease inhibitors were used. The Terrence Higgins Trust estimates the cost for HIV treatment in the UK for 1997/98 would be 10.3 million pounds sterling for monotherapy alone, 38.4 million pounds sterling for dual therapy, and 50.4 million pounds sterling if asymptomatic HIV-infected individuals receive dual therapy and symptomatic patients had triple therapy. For all patients to receive triple therapy, the cost would be 55 million pounds sterling.

In terms of each year of life saved, triple HIV therapy costs 10,000 pounds sterling compared with 25,000 pounds sterling for mammography and 100,000 pounds sterling for a coronary artery bypass.

Source: Scrip, 12 November 1996

The distribution of indinavir in the US is still restricted to one pharmacy - Stadlanders due to supply problems. ATP would be interested to hear from any doctors or pharmacists in the UK if difficulties arise accessing supplies of indinavir.

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Nevirapine/Indinavir Interaction Data Released



Boehringer Ingelheim have released interaction data on the combination of their NNRTI - nevirapine (NVP) and the protease inhibitor indinavir (IDV).

The following information is taken from a letter to investigators from Boerhinger Ingelhein dated 20th November 1996:


Nevirapine (NVP) is an inducer of hepatic cytochrome p450 metabolic enzymes predominantly of the 3A4 family. Thus, it has the potential to decrease the plasma levels of concomitantly administered drugs which utilise a similar metabolic pathway, such as the protease inhibitors. We have undertaken pharmacokinetic interaction studies with the three currently available protease inhibitors to define the interactions. Data from the NVP/saquinavir interaction study have been recently released to you (see ATPs Doctor Fax Issue 9) and the preliminary NVP/ritonavir interaction data should be available in January. Detailed below is the preliminary report on the NVP/indinavir interaction study which we have just completed.

The study included 24 HIV-1 infected individuals who received indinavir (IDV) for seven days followed by the addition of nevirapine (NVP) in the recommended dose escalation method for 28 days.

Results

In the 19 patients with evaluable data, coadministration of IDV with NVP resulted in a reduction in IDV plasma levels. The preliminary results indicate that coadministration of the two drugs resulted in a 28% mean reduction (p<0.01) in IDV AUC values, an 11% reduction (p<0.05) in IDV peak concentrations (Cmax) and a 38% reduction (p<0.01) in IDV trough concentrations (Cmin). Compared to historical controls, a nonsignificant reduction (<10%) in NVP AUC plasma concentrations was observed during combination therapy with IDV.

Safety

In general the combination of IDV + NVP has thus far been well tolerated. Of the patients completing the pharmacokinetic phase (n=19) plus withdrawn (n=5), two patients (8%) discontinued due to a rash that was attributed to NVP. These rashes were mild to moderate and resolved after discontinuation of study medication. The other three withdrawals were due to: kidney stone after 1-day on IDV, protocol noncompliance, and self withdrawal.

Discussion

With both NVP and IDV there is a relationship between dosing and antiviral activity. Increased resistance to indinavir has been observed in studies where IDV has been observed in studies where IDV was administered as monotherapy in doses less than the recommended 2.4 grams per day.

It is not known how NVP in combination with IDV may contribute to the suppression of resistance to IDV. Likewise, the effect on the development of resistance to NVP when IDV is coadministered has not been established. Cross resistance between NVP and IDV is unlikely because the enzyme targets are different.

In this drug interaction study, plasma levels of IDV coadministered with NVP were lower than plasma levels of IDV given alone. To adjust for the observed pharmacokinetic interaction, a dose increase of IDV to 1000mg q8h should be considered when IDV is given with NVP 200mg b.i.d. This may result in an IDV plasma pharmacokinetic profile that more closely resembles IDV 800mg dose administered without NVP. Currently there is not enough data to establish that the short term or long term antiviral activity of IDV 1000mg g8h with NVP 200mg b.i.d will differ from that of IDV 800mg q8h with NVP 200mg b.i.d. Thus the potential benefit of a dose increase of IDV (e.g., increased antiviral activity) must be evaluated with other issues (e.g., potential adverse events, diminished compliance, and increased drug costs).

We understand that the clinician must balance the pharmacokinetic data with issues that influence the optimal management of each individual patient. Although there is no definitive clinical recommendation, we are reporting these data in an effort to communicate the most current information on the use of NVP and IDV in combination.

Maureen Myers, Ph.D.
Clinical Research, Virology
Boehringer Ingelheim.

Plasma levels correlate well with risk of resistance to ritonavir and lower doses of IDV in initial studies were associated with more rapid failure of IDV therapy. This raises concerns over the coadministration of IDV and NVP. Increasing IDV dose whilst feasible, has obvious cost implications. The interaction of IDV with delarvirdine (another NNRTI soon to be available in expanded access studies in the UK) is not significant. Details of expanded access to nevirapine in the UK are awaited.


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Small Intestinal Disease Impairs Zidovudine Absorption



Small intestinal disease in AIDS patients may reduce the absorption of zidovudine, U.K. investigators report. They recommend careful evaluation of patients with HIV enteropathy who are on low-dose zidovudine regimens to avoid the danger of under treatment.

"Little is known about the influence of small intestinal disease in HIV infection on absorption profiles," according to Dr. Moses S. Kapembwa of Northwick Park Hospital in Middlesex and colleagues. Dr. Kapembwa compared the peak plasma zidovudine concentrations in nine AIDS patients who had chronic diarrhoea/wasting syndrome "...confirmed by reduced fat absorption..." with peak zidovudine concentrations in five AIDS patients with normal fat absorption. In all 14 subjects, measurements were made following administration of a single oral dose of 5 mg/kg zidovudine.

Dr. Kapembwa found that the subjects with diarrhoea/wasting syndrome had reduced peak plasma concentrations and delayed time to maximum plasma concentration of zidovudine compared with the subjects without diarrhoea/wasting syndrome. These preliminary findings suggest that "...assimilation of the drug might be slower in patients with AIDS-associated [small intestine disease]."

Dr. Kapembwa cautions that the clinical implications of these findings remain unclear due to the small size of the study and the absence of any significant differences in the area under the plasma concentration-time curve of zidovudine or the glucuronide metabolite of zidovudine. And he acknowledges that several other factors may impair zidovudine uptake, such as altered hepatic metabolism, physicochemical properties of zidovudine, plasma protein binding and gastric acid secretory failure.

Ref: AIDS 1996;10:1509-1514.
 Source: Aegis

Studies on the effect of diarrhoea on absorption of protease inhibitors is underway.


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Why Isn't Glaxo's New AIDS Drug Ready Yet?



While the new AIDS drugs known as protease inhibitors became available in less than five years, a drug being developed by Glaxo Wellcome was discovered in 1989 but is not expected to be approved before mid-1998. AIDS activists have been demanding access to the drug, known as 1592, and have charged the company with delaying its development to protect the sales of its older AIDS drugs, AZT and 3TC, whose combined revenue is expected to reach $600 million this year. The new drug is in the same class as the two older drugs, but it is 10 times more potent in vitro than AZT with apparently better tolerability. Glaxo contends that additional safety trials are needed before 1592, which is in the second of three phases of clinical trials, can be made available under a "compassionate access" program.

Source: AIDS Daily Summary

Further trials with 1592U89 are expected to include the UK. Expanded access programmes are eagerly awaited.


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CONFERENCE REPORT




Birmingham UK Drug Therapy Conference -- Early Report



The important 3rd International Congress on Drug Therapy in HIV Infection took place in Birmingham, UK, November 3-7. There was much interest in studies relevant to the complete suppression of HIV replication by drugs. A small but widely discussed study at the University of Amsterdam found that antiviral treatment which reduced viral load to undetectable levels in the blood, also reduced viral load to undetectable levels in lymph tissue. This was found in six out of six patients in a substudy of a larger trial. The lymph tissue was taken by a biopsy of the tonsils (which is much less invasive than the conventional procedure of removing a lymph node), before starting treatment and again after six months of treatment.

Researchers at the University of Minnesota developed the methodology to measure HIV in lymph tissue from tonsils; see recent paper by Haase AT, Henry K, Zupancic M and others, "Quantitative Image Analysis of HIV-1 Infection in Lymphoid Tissue," SCIENCE, November 8, 1996, pages 985-989.

Undetectable HIV viral load in the lymph nodes does NOT mean that the virus has been eradicated -- only that it is not actively reproducing. This viral load test only looks for viral RNA in plasma/tissue; it does not detect the viral DNA that is still in the patients' cells -- ready to start up the infection again if the drugs are stopped. No one knows whether or not all these cells will eventually be eliminated by the body, if replication can be stopped for long enough.

While the replication of the virus is being completely suppressed in plasma and lymph nodes, drug resistance apparently does not develop over up to one year follow up. The virus develops resistance when it is able to reproduce to some degree in the presence of the drugs.

These results are not surprising, as there have long been indications that if viral replication is being suppressed in the blood by antiretroviral drugs, it is also suppressed in the lymph nodes (where there is much more HIV replication than in the blood., No one would expect the drug resistance of the virus to increase if the virus is not reproducing. But it is important to get direct evidence, since these questions are central to the interpretation of viral load tests and the management of therapy.

Note: The drug combination used in this University of Amsterdam study was ritonavir, AZT, and 3TC, in volunteers who had not used any antiretroviral before. However, there is nothing special about this particular combination; all evidence suggests that what is important is reducing the viral replication essentially to zero and keeping it there, using whatever drugs can do so for a particular patient. Similar suppression of replication has also been achieved with other combinations using different protease inhibitors, two protease inhibitors together, -- or even no protease inhibitor at all.

One main problem is that some patients are more difficult to treat -- especially those with more advanced HIV disease, those who have already developed resistance to existing antiretrovirals, and those who cannot tolerate the drugs. This is why the problem of HIV treatment is not solved, despite the good results in some people. We need continuing development of better drugs -- with stronger and more durable antiviral effects, and/or less toxicity, and/or different resistance profiles than existing treatments, and/or drugs which may not be superior on the average but do work for some people when others treatments do not. And then of course there are still the economic barriers of getting effective treatments to those who need them.

More work is also needed on measurement of HIV in lymph tissue, since the most sensitive tests are quite difficult to do at this time.

There has long been an ongoing debate about the importance of aiming specifically for complete suppression of viral replication, vs. being willing to compromise on partial suppression due to practical concerns of toxicity, cost, and onerous compliance with regimens of three drugs or more. Professional opinion now seems to be moving more strongly toward the importance of complete suppression whenever antiviral therapy is used, because of the danger that otherwise the patients' virus will develop resistance to the drugs one by one, and each drug in turn will be lost for that person. This probably means that when therapy is begun, it will usually be with three or more drugs started together (instead of starting with one or two, then adding other drugs when the first ones fail); those who have already used antivirals will need to start or add combinations of at least two new drugs they have not seen before. What counts is keeping the viral load essentially at zero, whatever treatment that requires, because otherwise the virus will eventually escape the control of the drugs.

Extending and applying these principles to the treatment of many different patients in different situations, given the limitations of the drugs available and the practical limitations imposed by the difficulties of therapy, will be a central challenge in AIDS medicine for the next several years.

Source: AIDS TREATMENT NEWS No. 259 - November 15, 1996. John S. James.

The goal of below detectable is obviously a moving target with development of new generation assays now measuring below 20 copies/ml. Setting unrealistic holy grails such as achieving undetectable may lead to significant psychological morbidity amongst the moderate successes or failures. This article also ignores replication outside plasma and lymph. What about CNS, genital tract or other suspected sanctuary sites - resistance may arise from continued replication in these areas.


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OPPORTUNISTIC ILLNESS




Itraconazole: An Alternative For Oral Candidiasis In AIDS Patients



Canadian researchers say that itraconazole cyclodextrin, known as oral solution, appears to be an effective alternative treatment for fluconazole-refractory oropharyngeal candidiasis in HIV-positive patients, and should be tried before resorting to amphotericin B.

Dr. Peter Phillips of St. Paul's Hospital in Vancouver, BC, and colleagues evaluated 34 HIV-positive patients with oropharyngeal candidiasis that was refractory to fluconazole. Following daily oral dosing of 200 mg itraconazole solution for 2 weeks, 65% of the subjects had a clinical response. Of these, 36% had a complete response and 64% a partial response.

Eleven subjects who responded to itraconazole continued with follow-up. Dr. Phillips reports that relapse occurred within 2 months in 4 of these patients. Overall, itraconazole was well tolerated by the subjects.

Dr. Phillips concludes that "...itraconazole solution appears to be an effective treatment for fluconazole-refractory [oropharyngeal candidiasis], and [the findings] suggest that it may be active both topically and systemically." He also recommends that, since itraconazole is less toxic and easier to administer than intravenous amphotericin B, it should be considered prior to amphotericin B salvage therapy.

Ref: AIDS 1996:10:1369-1376.
 Source: Aegis

Fluconazole is most active against C. albicans strains. Itraconazole and ketoconazole have broader activity against C. glabrata and C. cruzei strains.

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PROGNOSTIC INDICATORS



Beta-2-microglobulin Levels Soon After Seroconversion as Predictor of Course of HIV Infection



The long-term clinical course of HIV may be predicted by serum beta-2-microglobulin levels soon after infection, according to a team of British investigators.

Dr. Andrew N. Phillips and others from the Royal Free Hospital School of Medicine in London evaluated beta-2-microglobulin levels in frozen serum samples obtained from 63 haemophiliac patients an average of 4.9 months after HIV seroconversion.

Over the following 10 years, patients with higher initial beta-2-microglobulin values "...tended to develop severe immunodeficiency/AIDS more rapidly than those with lower levels." Independent of this effect, age also predicted a more rapid course of the disease.

These two factors, older age and high serum beta-2-microglobulin, may be used to "...identify a group of patients very early in HIV infection in whom the prognosis is particularly poor." Dr. Phillips suggests that this subgroup "...requires close monitoring and consideration for early antiretroviral therapy," since the benefits of such treatment will likely to outweigh the risks in these patients.

Ref: J AIDS 1996;13:262-266.
 Source: Aegis.

Although this study is of interest, beta-2-microglobulin has been superceded by viral load and has been shown to be a poor treatment marker.


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Right Ventricular Function Severely Impaired In AIDS Patients



French researchers say that right ventricular (RV) alterations in AIDS patients are common and "...even more frequent than previously reported by echocardiographic studies." They also found "...compelling evidence that RV function is severely impaired in AIDS subjects."

Using cine-MRI, Dr. Enrique Casalino and colleagues at Bichat-Claude Bernard University Hospital in Paris performed a prospective blinded study to assess right ventricular and pulmonary circulation in 13 asymptomatic AIDS patients and 10 normal controls.

They found that "...AIDS patients had significantly increased RV end-diastolic and end-systolic volumes and decreased RV ejection fraction." Overall, the findings were "...consistent with predominant RV involvement in AIDS patients."

Based on their current observations, the researchers believe these patients may have "... pulmonary haemodynamic disturbances with adverse effects on RV structure and function." They conclude that "...pulmonary systolic overload is the most likely explanation for RV modifications in AIDS patients."

Ref: Chest 1996;110:1243-1247.
 Source: Aegis

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OBSTETRICS


Universal Antenatal HIV Testing Is Feasible



British researchers believe the introduction of a universal approach to antenatal HIV testing may be feasible.

Dr. Danielle Mercey of the University College London Medical School and colleagues reviewed the results of a universal voluntary antenatal HIV testing policy introduced to women attending an antenatal clinic at a London teaching hospital. Dr. Mercey reports the results from 1,374 women seen over a 49-week period.

She found that "...before the introduction of the new testing policy fewer than 10 women per year had an HIV test." After the introduction of the new policy, 41% of the women were tested for HIV. Women of caucasian and Mediterranean ethnic origins and those who had fewer previous live births were more likely to have an HIV test.

Two women tested positive, for a prevalence rate of 0.36%. Based on these results, Dr. Mercey concludes that "...universal voluntary antenatal HIV testing can be undertaken and can detect previously undiagnosed HIV positive women."

"Currently, antenatal screening policies are extremely variable across the United Kingdom," comments Dr. J. R. Smith and colleagues from the Chelsea and Westminster Hospital in London. "Many units offer no screening, some offer selective screening...and a few...offer universal testing to all pregnant women."

They recommend that women in high risk areas be informed that unless they object, they will be tested for HIV. At this time, the women should receive an explanation of the benefits of treatment to the infant if the HIV test is positive.
Women at higher risk should also receive extensive pre-test counselling. They believe this policy "...will improve patient care without compromising either the General Medical Council's guidelines on antenatal testing or the women's confidentiality."

Ref: Br J Obstet Gyn 1996;103;1059-1060,1129-1133.
 Source: Aegis

Availability of HIV Testing for Pregnant Women



In 1993-94 one in 570 women in London delivering a live baby was infected with HIV and more than 80 per cent remained undiagnosed during pregnancy. If a woman is aware of her HIV status during pregnancy there are interventions that reduce the risk of the baby becoming infected, by using antiretroviral therapy and by avoiding breast-feeding. In 1994 the Department of Health published guidelines recommending that antenatal HIV testing should be more widely available. Results of information gathered indicates that antenatal HIV testing services in London are failing to identify infected women during pregnancy and this situation must be improved.

Source: Nursing Times 13 November 1996

National guidelines on HIV testing during pregnancy are currently being prepared by The Royal College.


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PAEDIATRICS




Paediatric AIDS Prognosis Improved By New Clinical Staging System



A prognosis-based clinical staging system for HIV-infected infants has been developed by Dr. Brian W.C. Forsyth at Yale University and colleagues, which they say will be "...beneficial in advising parents about an infant's prognosis, therapeutic decision making, and stratification for clinical trials."

"Unlike HIV-infected adults, perinatally infected children quickly begin to have symptoms," the researchers point out in a paper in the November Journal of Paediatrics. Their staging system is based on clinical manifestation and age at presentation of HIV-related conditions, based on the recognition that "...symptoms develop early and that different manifestations of disease are associated with different risks of early death."

From a review of the data on 75 HIV-positive infants, Dr. Forsyth defined clinical stages of infection that correlated with prognosis and time of death. "As in other studies, children with encephalopathy, Pneumocystis carinii pneumonia, and other opportunistic infections had the worst prognosis, and were categorised as having stage IV disease. Children with one or more serious bacterial infections, anaemia, thrombocytopenia, hepatitis, persistent oral candidiasis or persistent fever were classified as having stage III disease. Children with hepatomegaly, splenomegaly, failure to thrive or persistent diarrhoea were assigned to stage II disease. Children with lymphadenopathy or without symptoms were designated as having stage I disease.

"It is striking," Dr. Forsyth concludes, that "...even by 6 months of age, clinical information can be used to distinguish between children who are likely to do well, at least for a number of years, and those whose prognosis is poor." The clinical importance of this information, he added, is that physicians can be "fairly optimistic" in advising the parents of children with stage I or II disease. Conversely, physicians need to be "more guarded" for children with stage IV disease.

In an accompanying editorial, Dr. Vas M. Novelli of the Great Ormond Street Hospital for Sick Children in London reviews the findings of Forsyth et al. Dr. Novelli agrees that they have "...a simple system that should prove useful both for early discussion about prognosis and for identification of those infants who fall into the poorer prognostic groups...and should benefit from a more aggressive treatment regimen."

However, Dr. Novelli adds that "...the proof...will be in the usefulness of the current system when it is applied to various large cohorts of HIV-infected infants in the United States and Europe."

Ref: J Pediatr 1996;129:623-625,648-655.
 Source: Aegis

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EPIDEMIOLOGY




Prevalence Of HIV Infection Rising In Central London



British researchers report that in the last two years the number of HIV-positive patients seen in their inner-city emergency department has increased by about a third.

Between 1992 and 1993, researchers estimated an HIV infection rate of 1 in 77 patients who were anonymously tested at St. Mary's Hospital, Paddington. Dr. Mark Poznansky and colleagues repeated this analysis for the period between 1994 and 1995.

Among all patients between the ages of 16 and 45 years, they found the HIV-positive rate had risen to 1 in 30. Most of the HIV-positive patients were men between the ages of 26 and 45 years. And if they required hospitalisation, most of these patients did not report their HIV status, when known, to staff members.

"There is a belief that HIV has plateaued or is actually declining," Dr. Poznansky said, "...but our study indicated that it may be premature to believe this in view of the high detected HIV prevalence in young adults attending this Accident and Emergency Department."

Ref: J Accident Emerg Med 1996; 424-425.
 Source: Aegis

According to the Dept. of Health AIDS deaths in the UK fell in 1995 relative to 1994 probably reflecting peak of new infections in the 1980s. Concentrations of seroprevalence around certain inner city units may not reflect national trends.

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AIDS Epidemic Levels In Europe: Data Conflicting



A Paris-based epidemiologic centre reports that the AIDS epidemic in Europe appears to be stabilising. But officials at the European Centre for the Epidemiological Monitoring of AIDS caution that this information should be carefully interpreted, according to a recent article in the journal Nature.

Within the 45 member countries of the World Health Organisations European group, 13,310 cases of AIDS were reported in the first 6 months of 1996. This brings the total number of cases reported in this region since the beginning of the epidemic up to 174,260.

A plateauing of the number of new HIV infections among homosexuals is primarily responsible for the stabilisation seen in northern European countries over last 2-to-3 years, the article continued. Although the overall rates are levelling off in Europe as a whole, in southern European countries, such as Italy and Spain, there is no evidence of stabilisation of the epidemic. In these countries, new cases of HIV infection among injection drug users are thought to be responsible for the increase in incidence.

Ref: Nature 1996;383:755.
 Source: Aegis

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