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Report from the Third International Conference on Drug Therapy in HIV Infection
Birmingham, United Kingdom

November 1996

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

This MEMBERFAX is brought to you by the Journal of the International Association of Physicians in AIDS Care

For the full conference report, visit IAPAC's AIDSCAN

Contents
Nelfinavir update
Nevirapine update
Ritonavir-saquinavir update
Glaxo Wellcome pipeline
Kaposi's sarcoma
Mycobacterium avium complex
Pneumocystis carinii pneumonia
Cytomegalovirus
Tuberculosis


Nelfinavir update

Since last year's announcement of the general safety and effectiveness of Agouron Pharmaceuticals' protease inhibitor nelfinavir, clinicians and patients alike have awaited further news of the drug's efficacy and availability. With nelfinavir now available through an expanded access program and new trials now underway, encouraging data are accumulating rapidly.

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Combination trials of nelfinavir and stavudine (d4T) began some months ago and have produced good efficacy and tolerability results. On that basis and encouraged by the results of Bristol-Myers Squibb's trial of didanosine (ddI)-stavudine combination. Louise Pedneault, MD, of Bristol-Myers Squibb, reported on the safety, tolerability, and antiretroviral effect of the triple combination of nelfinavir, ddI and d4T in 22 patients who had at least 10,000 copies of HIV RNA, with no limits on CD4 counts. Eight weeks' data was available from a single-arm, open-label trial which used full doses of each drug. Each drug was begun separately, starting with the nelfinavir. The median CD4 count was 315, and median HIV RNA level was 4.75 log (56,000 copies). Reported adverse events were limited, with 15 participants reporting loose stools and another three reporting grade-2 diarrhea, which was controlled with imodium.

By week eight, 17 participants had experienced median viral load reductions of 1.7 logs and median CD4 increases of 90-100 cells. Pedneault concluded that the combination of nelfinavir, ddI, and d4T showed relatively safe and potent antiretroviral activity and that ddI's antacid buffer had had no effect on the pharmacokinetics of nelfinavir.

Amy K. Patick, PhD, of Agouron, then presented a detailed analysis of the resistance and potential cross-resistance patterns of nelfinavir. Whether and to what extent HIV develops cross-resistance to other protease inhibitors once a patient has used one of these drugs has been a hotly debated issue since this class of drug entered large-scale trials a year ago.

During a genotypic analysis of the HIV protease from 58 patients (52 on nelfinavir monotherapy, 6 on the combinaton of nelfinavir and d4T) Patick, in collaboration with Dr. Martin Markowitz, identified a previously undescribed mutation (D30N). Mutations commonly described for other inhibitors were never observed in patients treated with nelfinavir for over one year. Isolates containing D30N which had high-level resistance to nelfinavir were fully susceptible to all other protease inhibitors including GW141W94.

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Nevirapine update

At last July's International Conference on AIDS, considerable excitement greeted the news that, in certain combinations, Boehringer-Ingelheim's non-nucleoside reverse transcriptase inhibitor nevirapine (NVP) demonstrated antiretroviral activity similar to that of some protease inhibitors. In Birmingham, Brian Conway, MD, head of the clinical retroviral laboratory at the British Columbia Center for Excellence in HIV/AIDS, reported on one of the most effective combinations utilizing nevirapine: nevirapine/zidovudine (ZDV)/didanosine (ddI). Conway and his team are members of the INCAS (Italy Netherlands Canada Australia States) Study Group.

The study randomized 151 antiretroviral-naive, asymptomatic, HIV-positive participants to three arms: nevirapine plus ZDV plus ddI, ZDV plus ddI, or ZDV plus NVP. The study lasted for one year and used full doses of each drug. Mean CD4 count at study entry was 376 cells (range, 200-600), and mean HIV RNA level was 25,704 copies. After one year, participants gained an average of 50 to 100 CD4 cells, while those on the triple combination gained more than 150 cells. Half of those receiving triple therapy had viral load reductions that fell below the detection limit of 200 copies. In comparison, only 11 percent of those receiving ZDV and ddI fell below 200 copies, and none of those on ZDV plus NVP fell below that detection limit.

A subset of Canadian participants were retested--using both their plasma and their lymph tissue--with the more sensitive Roche Amplicor assay, which can detect as few as 20 copies of HIV RNA. Fifty-one percent of those on the triple combination had fewer than 20 copies of HIV RNA; 12 percent of those on ZDV plus ddI fell beneath that limit; and none of those on ZDV plus NVP fell beneath it.

Results of this trial could have implications for planning antiretoviral strategies. G. Skowron, MD, of the Brown University School of Medicine in Providence, Rhode Island, said that results like these may be applicable for clinicians and patients interested in a "protease-sparing strategy" that would wait to use this powerful class of drugs when they are more needed and when newer generations of protease inhibitors may prove more tolerable. And Conway reported that a small number of patients in the INCAS study had stopped taking ddI after their HIV RNA levels had dropped below the detection limit--and remained below it. Conway said that if there is any implication of this small bit of evidence, it may be two-fold: If you're going to be noncompliant with an antiretoviral regimen, wait until your HIV RNA level falls below the assay's ability to detect it. He further suggested that it may imply that a three- or four-drug induction therapy may be able to be followed by maintenance therapy with two drugs.

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Ritonavir-saquinavir update

Everyone knew that it would happen sooner or later, and the early evidence indicates that the idea of combining two protease inhibitors may be a good one. Both ritonavir (RTV) and saquinavir (SQV) have demonstrated in independent trials that they can prolong survival and slow HIV disease progression. Saquinavir has been plagued by its low oral bioavailability, but when it is administered with ritonavir, its area under the curve (the time and amount of drug that are actually available) increased by more than 20-fold in healthy volunteers.

Now a pilot study of ritonavir-saquinavir combination therapy is underway, with 20 weeks of data available for some study participants. Some 140 participants with CD4 counts of 100-500 were enrolled. Average viral loads were in the 30,000-40,000 range. Subjects could have no previous protease inhibitor experience and had to discontinue any reverse transcriptase inhibitors. Participants were randomized into four open-label arms:

  • RTV 400mg bid plus SQV 400mg bid;
  • RTV 600mg bid plus SQV 400mg bid;
  • RTV 400mg tid plus SQV 400mg tid; and
  • RTV 600mg bid plus SQV 600mg bid.
Five participants have dropped out of the second arm due to drug intolerance.

Multiple HIV mutations are needed for resistance to RTV to develop, but sensitivity to SQV is retained even in the presence of those mutations, said William Cameron, MD, of the University of Ottawa and Ottawa General Hospital. Maintaining high RTV trough levels delays development of those mutations that can lead to resistance, and RTV itself sustains high trough levels of SQV. Liver irregularities that can occur with this combination are reversible with termination of treatment.

Eighty to 90 percent of participants in the twice-a-day regimens who were evaluated at week 20 showed HIV RNA levels below 200 copies. CD4 increases in the first two arms ranged between 65 and 135 by week 20 and reached about 115 for both the third and fourth arms by week 12. Recommended dosing regimen remains to be determined. And Cameron cautioned that no one should be tempted to make firm judgments about efficacy and durability of effect on the basis of 20 weeks' data.

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Glaxo Wellcome pipeline

Two new antiretrovirals from Glaxo Wellcome are likely to make major contributions in the fight against HIV disease in the near future. Stephen LaFon, of Glaxo Wellcome, presented early data on the company's second-generation nucleoside analogue, 1592U89. LaFon said that the drug has exhibited marked synergy in vitro with zidovudine (ZDV), nevirapine, and Glaxo's protease inhibitor, 141W94. It has shown limited or no cross-resistance with other nucleoside analogues, and so far seems to have excellent blood-brain barrier penetration. Preliminary results of a phase 2 study showed that 1592, in combination with ZDV, yielded reductions of 1.84 to 2.11 logs in viral load and CD4 increases of 84 to 116. Most common adverse events were nausea, headache, asthenia, and rash.

Nathan Clumek, MD, of the Free University in Brussels, briefly discussed 141W94. A phase I/II dose-ranging study in 42 HIV-positive volunteers yielded these data at four weeks: HIV RNA reductions of 0.58 to 1.95 logs and CD4 increases of 64 to 110 cells. These effects corresponded to increasing doses. The most common adverse effects were mild diarrhea/loose stools, rash, and headache. In vitro passage experiments have produced resistance not found in other protease inhibitors.

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Kaposi's sarcoma

With the increasingly clear association of human herpes virus-8 (HHV-8) with Kaposi's sarcoma (KS) and a growing array of chemotherapies, researchers and clinicians alike are becoming more hopeful that this once-rare form of cancer can be brought under control. The strong association of HHV-8 with KS may, in fact, open the way to control the spread of the disease from one individual to another. Robin Weiss, PhD, Institute of Cancer Research in London, asserted that the presence of HHV-8 is highly predictive for development of KS. Some 75 percent of those whose blood contained evidence of HHV-8, he explained, went on to develop KS within five years. He called for urgent development of a good, commercially available antibody assay to screen those who may be at risk for developing the tumor.

Ronald Mitsuyasu, MD, University of California, Los Angeles, offered an overview of current and upcoming KS therapies, focusing on those that offer the greatest potential for success. He pointed to retinoic acids, vesnarinone, and IL-4 as cytokine modulators that may control the development and growth of KS tumors. Some of the greatest interest among patients and clinicians focuses on today's improving anti-HIV treatments. There have been anecdotal reports of complete remissions among individuals taking protease inhibitors, and there has been some association between ritonavir and reduced KS tumors. How to use local therapies, both as mono- and combination therapies, for existing KS lesions is becoming clearer. Paclitaxel, already approved to treat other cancers, has demonstrated a 65 percent response rate against KS tumors, although it can be accompanied by neutropenia, alopecia and rash.

Misuyasu suggested a four-point strategy for managing KS:

  • optimize antiretroviral therapy, with a triple combination plus alpha interferon;
  • treat OIs, some of which can stimulate KS growth;
  • determine the extent of the KS and the debility caused by it; and
  • treat the tumors themselves with appropriate chemotherapies or radiation. For advanced patients, this could mean the use of liposomal antracyclines. The liposomal doxils, he said, seem to have an edge in effectiveness.

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Mycobacterium avium complex

Disagreement continues around how to prophylax for the illnesses caused by Mycobacterium avium complex (MAC), although treatment of the disease itself has become a little clearer. The risk of developing MAC rises as CD4 counts fall below 100, and the US Public Health Service recommends that prophylaxis begin at a CD4 count of 75. Richard Chaisson, MD, The Johns Hopkins University in Baltimore, pointed to studies demonstrating the superior ability of either clarithromycin or azithromycin--as opposed to rifabutin--to prevent development of MAC. However, a substantial number of patients - 11 to 59 percent - for whom prophylaxis with either of the first two drugs fails will develop resistant organisms, making treatment of any subsequent disease more difficult. Decisions about whether to prophylax with clarithromycin or azithromycin must be made on an individual basis, taking into consideration the relative costs, which one works better, adverse individual reactions, and possible interactions with other drugs the person may be taking.

Treating disseminated MAC disease remains difficult. Chaisson warned that clofazimine may be harmful and not very effective. He prefers treating with a combination of clarithromycin (500mg bid), ethambutol (15mg/kg/day), and rifabutin (450mg a day), a regimen he says is active against clarithromycin-resistant strains. Interactions with other HIV-related drugs requires extremely careful administration of these drugs. Some examples: Ritonavir cannot be used at all with rifabutin. With indinavir, the rifabutin dose must be reduced by half. And patients using saquinavir and rifabutin should increase their saquinavir dose. Prophylaxis must be continued for life.

  • optimize antiretroviral therapy, with a triple combination plus alpha interferon;
  • treat OIs, some of which can stimulate KS growth;
  • determine the extent of the KS and the debility caused by it; and
  • treat the tumors themselves with appropriate chemotherapies or radiation. For advanced patients, this could mean the use of liposomal antracyclines. The liposomal doxils, he said, seem to have an edge in effectiveness.

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Pneumocystis carinii pneumonia

Prevention of Pneumocystis carinii pneumonia (PCP) has been one of the few real victories in the fight against HIV. Yet, in a disturbing number of cases, PCP manages to break through and cause illness, and PCP remains the most common OI affecting people with HIV. Calling into question the notion that P. carinii is found widely throughout the general population, Jens D. Lundgren, MD, University of Copenhagen, pointed to increasing evidence that P. carinii may be transmitted through the air. He suggested that it may be advisable to isolate PCP patients from others who are susceptible.

Acknowledging that new agents and better diagnostic techniques are urgently needed, Dr. Lundgren offered the following treatment recommendations:

  • For mild-to-moderate PCP, cotrimoxazole should be the first choice. If it fails or cannot be tolerated, second choices are a combination of clindamycin and primaquine or of trimethoprim and dapsone.
  • For severe cases, cotrimoxazole remains the first choice, followed by intravenous pentamidine.
  • Adjunctive administration of steroids - started within 48 hours of the antimicrobial therapy - in moderate-to-severe PCP can prevent lung inflammation and decrease the risk of rash that comes with the standard treatments. Steroids also can mask symptoms of other infections as well as cause hypothermia and reactivate syphilis.
  • He cautioned that mechanical ventilation for those failing treatment should be weighed very carefully, as it is associated with a poor survival rate.

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Cytomegalovirus

Within the last year researchers and clinicians have turned several important corners in managing cytomegalovirus (CMV). As the HIV epidemic has continued, symptomatic CMV has occurred with increasing frequency: With the use of highly effective prophylaxes for Pneumocystis carinii, toxoplasmosis, and Mycobacterium avium infections, more patients are surviving long enough at lower enough CD4 counts for CMV disease to manifest itself. Bruce Polsky, MD, of the Memorial Sloan-Kettering Cancer Center in New York, cautioned that clinicians must be careful not to overlook nonretinal sites of CMV disease. CMV in such sites can too easily be mistaken for other opportunistic infections, since the symptomatologies can substantially overlap. In particular, he pointed to CMV disease of the central nervous system and the gut as increasingly important symptoms to watch for, especially for patients with a history of retinal CMV or with high CMV viral loads.

Early analysis of viral isolates from people being treated with ganciclovir for CMV retinitis indicates that people with high-level resistance to ganciclovir will also have decreased susceptibility to later therapy with cidofovir. But low-level resistance to ganciclovir appears not to lead to reduced susceptibility to cidofovir. An in vitro study presented by Julie Cherrington, PhD, of Gilead Sciences, the maker of cidofovir, documented a clear difference between CMV isolates that were highly resistant to ganciclovir and those that had low-level resistance (Table 1). She defined low-level ganciclovir resistance as an IC50 value between 8.5 and 30 µM, mutation of the UL97 gene, but wild-type CMV DNA polymerase.

Table 1. Differences between low-level and high-level resistance to ganciclovir

Low-level resistanceHigh-level resistance
IC50 (µM)
8.5 to 30
> 30
UL07 gene
Mutant
Mutant
MCV DNA polymerase
Wild type
Mutant
In vitro suceptibility to cidofovir
Susceptible
Not Susceptible
In vitro suceptibility to foscarnet
Susceptible
Susceptible
Time on ganciclovir
Short-term
Long-term
Source: Julie Cherrington, PhD, Gilead Sciences.

Study participants with low-level resistance had been treated with ganciclovir for fewer than nine months. High-level resistance was signified by an IC50 > 30 µM and mutations of both UL97 and polymerase. People with high-level resistance had been treated with ganciclovir for more than nine months. In vitro analysis of the 17 isolates with low-level resistance to ganciclovir showed that they remained sensitive to cidofovir (IC50 < 2µM), whereas 11 high-level resistant isolates were no longer susceptible to cidofovir. Isolates with either low-level or high-level resistance to ganciclovir remained sensitive to foscarnet.

Cherrington also reported that decreased susceptibility to cidofovir has, so far, not correlated with a poorer clinical outcome. Among 16 individuals with relapsing retinitis who were treated with cido-fovir for more than two months, seven had decreased susceptibility to cidofovir. But the people whose isolates showed decreased susceptibility have not had faster progression of CMV retinitis than those whose isolates have remained sensitive to the drug.

Looking at resistance to foscarnet after three months of first-line treatment with the drug, Cherrington reported that none of five isolates tested had lost susceptibility to it. But six of 10 isolates from individuals treated with foscarnet for four months after initial ganciclovir therapy had decreased susceptibility to foscarnet. Cherrington said, however, that too little work had been done on resistance to foscarnet as first-line therapy to suggest that the drug should replace ganciclovir as the standard initial treatment for retinitis.

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Tuberculosis

HIV seropositivity and AIDS diagnosis are now recognized as the most potent risk factors for the development of Mycobacterium tuberculosis infection (TB), alongside the well-established aggravators of poverty and migration.

The interaction between TB and AIDS is not simply one of epidemiology. Kevin de Cock, MD, London School of Hygiene and Tropical Medicine in England, identified the following interplays between these two major public health conditions:

  • TB increases markers of immune activation;
  • TB increases levels of HIV-RNA;
  • People with HIV and TB have higher mortality than those without TB;
  • TB may accelerate underlying HIV disease (although TB may simply be a marker).
Given the dangerous synergy between the two conditions, de Cock proposed that greater attention be paid to prevention. He noted that in the UK, TB is the AIDS-defining illness for 27 percent of black Africans, yet only 8 percent of this population were on prophylaxis. By contrast, 40 percent of whites were on prophylaxis, while accounted for just 17 percent of this group's AIDS-defining condition.

One of the critical methods to prevent TB and MDR-TB outbreaks is to reduce transmission through good compliance with effective treatment regimens. The World Health Organization proposes using DOT (Directly Observed Treatment), and the success of this approach has been demonstrated. A study by Wilkinson (Lancet, 1992) showed that 89 percent of people on DOT completed therapy, compared with 18 percent not on DOT.

People who are immunocompromised, including those with HIV/AIDS, appear to be six times as vulnerable to acquiring MDR-TB and have a severely increased mortality. The development of MDR-TB may relate to the location of primary acquisition: prisons, shelters, hospital wards, family settings, and HIV and drug use clinics. For this reason, patients with MDR-TB should be isolated (preferably in negative pressure rooms) and all risky procedures should be restricted to areas where there are no people who are immunosuppressed. For example, nebulized pentamidine and bronchoscopies should not take place on open wards.

Those who have been exposed to MDR-TB may be started on post- exposure prophylaxis (PEP) of either ethambutol and pyrazinamide or ofloxacin/ciprofloxacin and pyrazinamide. It is important for PEP to use more than one drug in order to reduce future resistance that may occur should the individual go on to develop TB. Anton Pozniak, MD, at St. Mary's Hospital in London, argued forcefully against the practice of sequentially adding one drug to a failing treatment regimen. Prior therapy is a major determinant of MDR-TB, with 40 percent of people on 14 months of prior therapy developing resistance (compared with less than five percent of people on under two months therapy).

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For more summary data from the Third International Conference on Drug Therapy in HIV Infection, see IAPAC's AIDScan report.

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!



  
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This article was provided by International Association of Physicians in AIDS Care. It is a part of the publication Journal of the International Association of Physicians in AIDS Care.
 
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