ISSUE 55 - Conference Report Special

38th Annual ICAAC, San Diego
September 24-27, 1998

Editor Paul Blanchard

Medical Consultant




38th Annual ICAAC, San Diego, September 24-27, 1998

The Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) is an annual meeting on infectious diseases hosted by the American Society for Microbiology. HIV, other retroviruses and complications of AIDS occupies one of the fifteen conference tracks, although other presentations pertinent to HIV treatment may also be found in related tracks (i.e. Pharmacokinetics). Members of AIDS Treatment Project attended ICAAC to provide reports for our "Doctor Fax" and Positive Treatment News (PTN) as well as for the magazine Positive Nation.

Additional "next-day" conference summaries may also be found on the web page of the Healthcare Communications Group:

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Extended Data on Efavirenz Containing Regimens

24-week data from the DuPont Pharma study (DMP 266-006) of efavirenz (EFV) in combination with zidovudine (ZDV) and lamivudine (3TC) were previously reported at this years World AIDS Conference in Geneva (see ATP's "Doctor Fax" issue 51). Further data from this study, out to 36 weeks, were presented at the ICAAC meeting.

Patients entering this study were required to be naïve to all protease inhibitors, NNRTI's and 3TC. Baseline demographics revealed that participants had a mean CD4 count of 345 (±203) cells/mm3 and a mean log HIV-1 plasma RNA level of 4.77 (±0.57). Subjects were randomised to one of three arms:

The 24 week data presented at Geneva basically showed equivalence in both virologic and CD4 response between both the EFV and the IND containing triple arms. This was the first time such equivalent activity had been reported for an NNRTI containing regimen in a head-to-head comparison with a protease inhibitor based regime. Further, a subanalysis of patients entering the study with baseline viral loads >100,000 copies/mL also showed equivalence across the two triple combination arms.

The up-dated 36 week data for plasma HIV-1 RNA presented using the intent-to-treat last observation carried forward (ITT: LOCF) showed:

<400 copies/mL 85% 65% 65%
<50 copies/mL 66% 50% 52%
N= 154 148 148
Premature terminations 38 (25%) 61 (41%) 45 (30%)

The numbers of subjects who achieved below the level of quantification at both 50 copies and 400 copies/mL was statistically significant between the EFV/ZDV/3TC and the IND/ZDV/3TC arms (p£0.05). Mean change in CD4 cell count at 36 weeks was similar across the arms at approximately 150 cells/mm3.

Ref: Abstract I-103 Author: Paul Blanchard

This extended data on an efavirenz containing regimen continues to look promising. It does, however, have to be emphasised that this was an open-label trial with unresolved questions over the unexpectedly high drop-out rate in the IDV triple arm.

Apart from durability of viral suppression, other issues to be resolved with NNRTI's vs. PI's must be urgently addressed before any consensus might be reached on their utility in so-called "protease sparing" regimens:

  • Differences in t-cell recovery, lymphocyte TCR- beta repertoires etc?
  • Differences in lymph node clearance?
  • Differences in resolution of OI's (eg. KS, PML)
  • Longer term tolerability, effects on metabolism (body composition etc.)?

84 week data was also presented at the conference on the open-label study of the combination of efavirenz + indinavir (DMP 266- 003). A total of 59 patients were enrolled in the arm of this study to receive treatment with the combination of EFV/IND. Again, using the intent-to- treat, last observation carried forward (ITT: LOCF) method of analysis, 84 week data showed 74% of 53 subjects with a viral load <50 copies/mL and mean change in baseline CD4 cell count of approximately 250 cell/mm3. There were a total of 15 (25%) premature terminations by 84 weeks amongst those patients who had been initially randomised to EFV+IND. In general, resistance to both EFV (K103N) and IND was found in those patients who failed to maintain virologic suppression.

Ref: Abstract I-104 Author: Paul Blanchard

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Efavirenz in Paediatric HIV Infection

Investigators of the U.S. Paediatric AIDS Clinical Trials Group (PACTG), announced results at the ICAAC late breaker session of an interim analysis of the first paediatric study of efavirenz. The purpose of the study, known as PACTG 382, is to determine the safety, dosing and antiviral effect of efavirenz in combination with antiretrovirals in HIV-infected children. Efavirenz, when used in combination with nelfinavir and other antiretrovirals, suppressed HIV replication over a 20-week period in most children.

PACTG 382 is a Phase I/II multi-centre study evaluating a combination therapy consisting of efavirenz, the protease inhibitor nelfinavir and nucleoside reverse transcriptase inhibitors (NRTIs). As a safeguard, this highly intensive study was designed to closely monitor blood levels of efavirenz and nelfinavir. Drug doses were adjusted as needed.

A total of 57 children were enrolled in the study. Participants were younger than 16 years, had not been previously treated with protease inhibitors or NNRTIs, and were able to swallow capsules. The median age of the children was 8.0 years; the median CD4+ T cell count was 699 cells/mm3, and the median viral load was 10,000 copies HIV RNA/ml. NRTIs were continued or changed at entry as clinically indicated. Pharmacokinetic studies were carried out at weeks two and six. Efavirenz was given at a starting dose of 600 mg/m2 once a day in combination with nelfinavir at the currently approved dose of 20-30 mg/kg three times per day. To date, this combination has been well tolerated by most subjects.

The most common side effects were: rash (28.1 percent), which was seen more commonly in children than in adults; diarrhoea (15.8 percent); and abnormally low levels of neutrophils (8.8 percent), a type of white blood cell. The percentage of participants whose HIV RNA was less than 400 copies/ml was 3.5 percent at baseline, 51.9 percent at the second week, 60.0 percent by the fourth week, 75.0 percent by the fifth week, 78.4 percent by week 12 and 66.7 percent at week 20. This antiviral effect is comparable or superior to that observed with previously tested combinations of antiretrovirals in this patient population. Furthermore, once-a-day administration of efavirenz may make it easier for patients or caregivers to adhere to therapy. Additional follow- up through the full 48-week course of the study will be important to determine if the drop in viral load is long-lasting and if the regimen will be well tolerated in children over time.

The study directly contributed to accelerated Food and Drug Administration (U.S.) approval earlier this month of efavirenz as a treatment option for HIV-infected children.

Ref: Abstract LB-6 Source: Adapted from an NIAID/NIH press release.

This study is to be commended for it’s monitoring of blood levels of both efavirenz and nelfinavir. It should be noted, however, that although this allowed for dose adjustment at 6 weeks, 30% of children were still found to be receiving doses producing plasma levels outside of the defined therapeutic range. With PK characteristics and complex interactions of antiretroviral agents closely determining ability to control HIV-replication this adds to the body of data suggesting inter-individual variability in PK of many of these drugs may, in part, explain the differing effectiveness and durability seen between patients. When will concerted efforts be made to introduce therapeutic blood level monitoring into clinical practice?

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Fortovase BID Regimen in Combination

with 2 NRTIs or Nelfinavir plus 1 NRTI Charles Farthing, MD of the AIDS Healthcare Foundation in Los Angeles reported preliminary findings from a 48 week study of a comparison between Fortovase (saquinavir-sgc) taken 3 times per day plus 2 NRTIs versus Fortovase taken twice daily plus 2 NRTIs versus Fortovase twice daily plus nelfinavir twice daily plus 1 NRTI. Both treatment naive and NRTI-experienced individuals participated in this study. This study has,

The study analysis will include a pharmacokinetic study evaluating the BID dosing regimen by examining the AUC-24, Cmax and Cmin across treatment groups; a virologic substudy will evaluate and correlate the genotypic and phenotypic markers for resistance and cross- resistance in those with virologic relapse on both the TID and BID regimens; an immunological substudy will evaluate immunological markers of long-term response to TID and BID regimens; as well, the study will evaluate the immune function in long-term responders on the TID and BID regimens.

The plan is to enrol over 800 participants into 3 treatment arms, but this preliminary analysis is based upon 242 participants:

Baseline characteristics showed a mean viral load of 4.7 log (about 50,000 copies/ml) for each arm, the mean CD4 count was 300-335 cells. Preliminary withdrawals at Week 24 (N= 84/grp A, 81/grp B, 77/grp C)-- In group C there were more individuals who withdrew due to "refused treatment" (9 vs 4 in group A and 4 in group B), and more who withdrew due to "failure to return" (14 vs 7 in group A and 6 in group B). Farthing suggested that this may have been due to the high pill burden and higher GI side effects in group C. The total premature withdrawals reported by Farthing in the 3 arms are-- 19 in Arm A, 19 in Arm B, and 29 in Arm C.

A Pharmacokinetic (PK) substudy showed SQV plasma levels for AUC-24, Cmax, Cmin, and Cavg (concentration avg) were lower for individuals taking the TID (arm A) regimen in this PK study than for individuals taking the BID regimens in Arms B & C. The following data is the mean at week 12; group A- FTV 1200 mg TID (n=6), group B- 1600 mg BID (n=6), group C- 1200 mg BID FTV+1250 mg BID NFV (n=8).

AUC-24 (ng.h/ml) Cmax (ng/ml) Cmin (ng/ml) Cavg (ng/ml)
Arm A 18 108 2 054 182 755
Arm B 26 972 3 412 246 1 124
Arm C 29 702 3 136 309 1 238

To date 240 of the planned 800 or more patients have been analysed and 720 enrolled. In the intent to treat analysis at week 24 about 60% are < 400 copies/mL across all arms; about 40% are < 50 copies/mL. In an "observed" analysis, the CD4 increases were about 150 cells for each Arm at week 24.

Adverse Events--moderate to severe in >5% of patients per treatment group, and possibly or probably related to study treatment.

Adverse Event A (n=84)
Diarrhoea 6 7 17
Nausea 12 - 5
Headaches 8 - -

Farthing noted the higher incidence of diarrhoea in the nelfinavir arm, and the higher incidence of nausea and headache in the TID SQV arm versus the BID SQV arm.

Ref: Abstract I-105 Source: Adapted from a report by Jules Levin, NATAP.

The pharmacokinetics substudy seem to add support to the concept of BID dosing for saquinavir-sgc. However, with only 60% of patients achieving below the level of quantification for HIV RNA (<400 copies/mL) at 24 weeks, the virological response rate seems disappointingly low for the study population. With the data consisting of a mix of all sub-groups a more detailed and fuller analysis may be helpful to get a better impression of the potency of these different regimens.

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A Comparison of BID and TID Dosing of Nelfinavir

Interim results on this study at 36 weeks were previously reported at the 5th Conference on Retroviruses and Opportunistic Infections in Chicago this year (see ATP's Doctor Fax Issue 42).

At ICAAC, the European Nelfinavir Clinical Trial Group presented interim results at 48 weeks comparing twice daily and three times daily doses of nelfinavir in combination with d4T/3TC among 223 patients naïve to the study drugs and with less than six months prior antiretroviral therapy. At baseline, subjects had a mean HIV RNA of 5.1 log copies/mL, and mean CD4+ counts of 254 cells/mm3 in the TID arm and 273 cells/mm3 in the BID arm.

The original study design employed BID nelfinavir doses of 750 mg, 1000 mg and 1250 mg, compared with the standard dose of 750 mg TID. When another study subsequently demonstrated poorer virologic responses to 500 mg compared with 750 mg TID, this protocol was amended. Since November-December 1997, all the BID recipients have received 1250 mg doses of nelfinavir.

An on-treatment analysis at 48 weeks (n=165 on BID, n=59 on TID) revealed that both dosing regimens appeared equivalent with suppression of HIV RNA to below 400 copies/mL in approximately 80% of patients and to below 50 copies/mL in at least 68%. CD4 cell count rises were also similar at around 150 cells/mm3 for both dosing regimens. Further analysis of time to below level of quantification of HIV RNA, and duration of response also failed to differentiate between the treatment arms for up to the 48weeks for which data was presented. Both BID and TID dosing was well tolerated with diarrhoea being the main adverse event being reported. The group concludes "...the high response rate together with excellent durability and low incidence of side- effects justifies the continuation of this study".

Ref: Abstract I-216 Author: Paul Blanchard

In contrast to indinavir (see report in this issue), the data on BID dosing of nelfinavir from this study continue to support the possibilities of dosing twice daily.

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Micronutrient Deficiencies May Contribute to Ritonavir Intolerance

A retrospective chart review of 322 patients was performed by a group from Rhode Island to identify possible correlates of patient intolerance to ritonavir (RTV). Seventy-four patients met the inclusion criteria for the study of whom 26 had discontinued ritonavir due to intolerance (intolerant group, IG). Gastrointestinal symptoms accounted for 92% of patient intolerance. 42 patients were considered to have been tolerant to ritonavir (TG) while a further 6 patients had discontinued the drug due to virologic failure. Dose of RTV, body weight, body composition, nutritional status, and/or use of anabolic agents were all examined for their influence on the tolerability of RTV containing regimens.

77% of IG patients were found to have received full-dose (600mg BID) ritonavir while 69% of the TG received RTV/SQV (400mg of each BID). Nausea and vomiting were significantly more likely to have been experienced in the intolerant group. Low body fat at baseline was also found to be significantly more prevalent in the IG.

Interestingly, when micronutrient deficiencies at baseline were compared between the groups 58% of those in the IG had documented deficiencies compared to only 27% of the TG (p=<0.001). Nutritional supplement use was also found to be lower in the IG at 32% compared to 69% using supplements in the TG (p=<0.05). The group concluded that although important, RTV dose alone did not account fully for the difference in tolerance between the groups. Patients with micronutrient deficiencies and history of lower body fat at baseline were more likely to experience intolerance to RTV and more likely to discontinue its use. They added that nutritional supplementation may increase tolerance and reduce discontinuation rates seen with RTV use.

Vitamins C, E, B12, Folic acid and beta- carotene were among the micronutrients measured in this study.

Ref: Abstract I-89 Author: Paul Blanchard

An intriguing hint from this study that micronutrient supplementation when administering ritonavir may improve tolerability. The proof of concept would have to be a controlled trial of ritonavir initiated with and without supplementation. However, many may be tempted to use such a low cost, low risk strategy on the basis of the observations seen above.

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Trends in Costs of Care for Patients with HIV

Declining mortality and morbidity from HIV in the US and in Europe is now well established since the appearance and widespread use of HAART in the treatment of people with HIV. Those of us involved in patient care in the pre-HAART era can attest to the frequent need for hospitalisation and high utilisation of other costly medical interventions that defined patient care at that time. Cost of care and outcome data are becoming increasingly commonplace at scientific meetings these last two years in an attempt, it seems, to provide a context in which to evaluate the high cost of multidrug therapy. No study has been able to describe and measure all of the relevant cost and outcome variables that would be necessary for a complete understanding of the costs and benefits of HIV therapy as it continues to evolve.

Nevertheless, with each attempt to study this issue, a better economic understanding emerges which is most certain to drive public health policy and purchasing of healthcare. In the study by Lapins and colleagues, mortality rates and average monthly drug and non-drug costs for managed care members with HIV was examined from 1995-1997. Protease inhibitors and the use of triple combination therapy emerged during this time.

Clinical Partners (a national HIV case management company for managed care organisations) collected data on adult non- Medicaid/non-MediCal enrolee's in Texas and California from January 1995 through December 1997. The costs of medical services (drug, non- drug and total) were determined from amounts paid on claims or by imputed costs (costs not adjusted for inflation) for similar services when the services were capitated, and calculated on a member-per-month basis. Non-drug costs included hospital, professional, laboratory and homecare services. The patient population consisted of 100% insured Caucasian males, with no reported intravenous drug users.

The number of HIV members increased from 474 per month in January 1995 to 722 per month in December 1997, but the authors fail to identify the source of patient growth over this time (growing patient enrolment in health plans vs. declining mortality vs. increasing number of health plans under their management). Furthermore, there is no data regarding the changes in antiretroviral therapy over this time, so we are left to surmise that increases in drug costs resulted largely from appropriate and consistent use of combination antiretroviral therapy (perhaps an unsafe assumption). Despite these shortcomings, declines in mortality, non-drug costs and total cost were demonstrated over this time period, with an increase in drug costs:

HIV MPM Costs beginning 1995 HIV MPM Costs end 1997
Drug costs $226 Drug Costs $1072
Non-drug costs $1365 Non-drug costs $166
Total Costs $1472 Total Costs $1316
Mortality rate 4.8% (1 Q 95) Mortality rate 0.25% (4 Q 97)

(Upon statistical analysis, the rising trend in drug costs and the declining trends in mortality and non-drug and total costs had significant r values)

No causal relationship can be made in this study between the use of combination antiretroviral therapy and declines in costs and mortality. However it is quite plausible, in this demographically homogeneous employed patient population, that improvement in patient outcomes is derived from the availability of new and potent drug combinations. In agreement with the authors, future examinations of the economics of HIV care should consider all components of care as well as indirect costs such as costs to community services, employers, friends, families, and economic benefits in terms of productive years gained.

Ref: Abstract O-21 Coverage provided by Jim Thommes, M.D. Source: The Body

A further analysis of the impact of HAART on in-patient utilisation and costs by HIV-infected individualised enrolled in the Ryan White title II program was also presented during the late breaker session. This study concluded that for every $1 spent on antiretroviral therapy there was a corresponding $3 saving in inpatient cost.

Ref: Abstract LB-11

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Antiretroviral Drugs and Treatment Strategies

Indinavir - Merck Issues Warning on Twice Daily Dosing

Merck & Co., Inc., announced September 18th that it has discontinued the evaluation of twice- daily dosing regimens of its HIV protease inhibitor indinavir sulfate (Crixivan®) in combination with reverse transcriptase inhibitors (RTIs).

Merck recommends that patients in the twice- daily dosing arms in these studies be changed to a regimen with the approved dosing (800 mg every eight hours) of indinavir to ensure that they receive optimal therapy. Merck will continue to study twice-daily dosing of indinavir in combination trials with other protease inhibitors.

The Company had initiated two studies to compare the antiviral efficacy and tolerability of the approved 800 mg every eight hours dosing with twice daily dosing (1,200 mg every 12 hours) of indinavir. The first study (protocol 069) compared indinavir twice daily versus indinavir three-times daily, each in combination with the RTIs zidovudine (ZDV) and lamivudine (3TC), in patients starting anti-retroviral therapy. The second, a transition study, evaluated the two dosing regimens (indinavir twice-daily with RTIs and three-times daily with RTIs) among patients who had already achieved levels of virus below detection after six months on therapy with the approved three-times daily dosing of indinavir (800 mg every eight hours) with RTIs.

The decision to end these study arms is based on data from an interim analysis of the initial therapy study (protocol 069) at week 24, that showed that the three-times daily regimen was more effective than the twice-daily regimen in reducing levels of viral RNA to below detection (<400 copies/mL) in patients initiating therapy. At week 24, 91 percent of patients on the approved dosing regimen had achieved viral levels below 400 copies/mL, compared to 64 percent of patients on the twice-daily regimen.

The table below shows the vRNA analysis at weeks 16 and 24: Proportion (%) of Patients with vRNA < 400 copies/mL

Indinavir 800mg q8h Indinavir 1200mg q12h
(vRNA < 400 copies/mL) (vRNA < 400 copies/mL)
16 Weeks (n=287) 78% 72%
24 Weeks (n=87) 91% 64%

Double Protease inhibitor studies with Twice- Daily Indinavir Continue

Other studies now under way by Merck to evaluate the antiviral activity of twice-daily dosing of indinavir combined with other protease inhibitors dosed twice-daily, such as nelfinavir and ritonavir, are continuing.

Adapted from Company Press Release, Merck & Co., Inc.

Based on these findings, the company is encouraging everyone using twice daily dosing to switch back to 3-times daily.

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U.S. Approval of Efavirenz (SustivaTM)

The Food and Drug Administration has approved DuPont Pharma's efavirenz (Sustiva), a once-daily non-nucleoside reverse transcriptase inhibitor (NNRTI) for treatment of people with HIV.

Efavirenz has been approved in the U.S. for once-daily dosing to be used in combination with other antiretroviral drugs in both adult and paediatric patients.

Efavirenz can be taken once a day with or without food and will be available in 200 mg capsules for adult dosing (600 mg per day) and in 100 mg capsules and 50 mg capsules for paediatric dosing. The accelerated approval of efavirenz was based on analysis of plasma HIV- RNA levels and CD4 cell counts in controlled studies of up to 24 weeks in duration. At present, there are no results from controlled trials evaluating longer-term suppression of HIV-RNA with efavirenz.

Resistant virus emerges rapidly when NNRTIs are administered as monotherapy. Therefore, efavirenz must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen. Efavirenz therapy should always be initiated in combination with at least one other antiretroviral agent to which the patient has not been previously exposed. Safety data from clinical trials show efavirenz is generally well tolerated. The most significant adverse events associated with efavirenz therapy are nervous system symptoms, which are reported in approximately half of patients (dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming). The study discontinuation rate for nervous system symptoms was 2.6 percent. These symptoms occur early in treatment and generally resolve in most patients within a few weeks, according to DuPont.

DuPont warned pregnant women not to take efavirenz because animal studies indicated that there might be a risk of birth defects.

See ICAAC reports in this issue of the “Doctor Fax” for further data on efavirenz. Some physicians are using benzodiazepines or the tricyclic antidepressant trimipramine to help control the insomnia sometimes seen with efavirenz use. As with other medications found not to be tolerable, patients with long lasting side effects should consider a switch, perhaps to another NNRTI if this class of drug is considered to be essential to their combination regimen. One complication of taking efavirenz is that some users may falsely test positive for marijuana when drug-screening assays are used. These tests detect chemicals found in marijuana which are released into the urine. According to the manufacturer of efavirenz, DuPont, a confirmatory test (using gas chromatography) will clear up the matter by revealing the presence of efavirenz and not the chemicals found in marijuana. This information may prove useful to users of efavirenz who have to undergo drug testing for various reasons. (However, NOT a great way to "come out" as HIV-infected in the workplace - fail a drug test, but it's OK, “'s not cannabis, only your anti- HIV medication!"

Efavirenz is currently available to patients in Europe from the manufacturer DuPont Pharma through named-patient or expanded access studies depending on country. In the U.K. physicians requiring information on obtaining efavirenz should call Sylvie Dupin on 0800 731 4341 (tel), or 0800 731 3706 (fax).

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Combivir® Alert!

Discretion should be taken when considering modification of personal treatment plans with Combivir®. Some doctors may be confused about Combivir® and how it fits into anti-HIV therapy strategies. To illustrate this point, consider the following scenario: A man was taking a two-drug combination of ZDV (zidovudine, Retrovir®) and 3TC (lamivudine, Epivir®). He and his doctor began seeing a trend of increases in his viral load and decreases in his CD4+ cell count. His doctor wisely recommended that he switch to a new regimen. He then prescribed Combivir® and Indinavir (Crixivan®).

Combivir® is a combination pill form of ZDV +3TC. It is not a new drug. If people have been on ZDV+3TC, then switching to Combivir® is equivalent to continuing on ZDV+3TC. If someone is failing a ZDV+3TC combination regimen, they will not benefit from Combivir®. Essentially this man was put on indinavir alone, which may quickly lead to indinavir resistance and decreased or no benefit from subsequent protease inhibitors.

Source: PI Perspective 25, September 1998 "From Project Inform, for more information contact the Project Inform National HIV/AIDS Treatment Hotline, 800-822-7422."

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Sustained antiretroviral treatment response requires profound HIV suppression

An international team of AIDS experts says the recommended goal of lowering HIV levels to less than 400 copies/mL needs revising. The investigators report evidence from a controlled, randomised trial showing that "...suppression of [plasma viral load] below 20 copies/mL is necessary to achieve a long-term antiretroviral response."

Dr Julio Montaner of the University of British Columbia, Vancouver, and colleagues examined factors relating to plasma viral load suppression in 104 HIV-positive patients. The patients had a baseline plasma viral load >500 copies/mL and a plasma viral load nadir <500 copies/mL, were free of AIDS, and had CD4 counts between 200 and 600.

In the September 10th issue of the journal AIDS, the team reports that reducing plasma viral load down to "...below the limit of quantitation of the most sensitive assay currently available (20 copies/mL)..." substantially lowered the risk of "subsequent virologic failure."

Specifically, the risk of viral levels returning to 5,000 copies/mL or more was 0.05 for a nadir below 20 copies/mL, and 0.37 for a nadir between 20 and 400 copies/mL, relative to a nadir greater than 400 copies/mL.

Dr. Montaner and colleagues urge physicians managing HIV-positive patients to use the most sensitive assays available to quantify plasma viral load. They conclude, "Our data strongly support the need for a revision of the current guidelines for the management of HIV infection."

Ref: AIDS 1998;12:1619-1624. Source: CDC HIV/STD/TB Prevention News Update

This data, amongst others, has important implications for the availability and funding of HIV PCR viral load tests measuring down to lower levels of quantification (<20 copies/mL). It also adds impetus to treatment guidelines to pay closer attention to discussion of how to manage both those patients who fail to reach <400 copies/mL and those who are found to be persistently between 20 and 400 copies/mL.

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Caution: Should We Be Treating HIV Infection Early?

The current consensus among AIDS experts is for early and aggressive antiretroviral treatment for HIV-infected patients. However, Dr. Jay Levy of the University of California in San Francisco questions this approach.

In an editorial in the September 19th issue of The Lancet, Dr. Levy makes the case for reserving certain antiretroviral therapies for a later stage of infection. He stressed that he is not referring to patients in the acute or primary stage of HIV infection, who can greatly benefit from dramatic suppression of viral load at this time, but for the majority of patients who present several months or years after seroconversion. For these patients, the published guidelines urge commencement of triple drug therapy when CD4 counts drop below 500 per microliter and HIV RNA load exceeds 5,000 copies/mL. It is these numbers, rather than the patient's clinical status, he points out, that dictates the therapeutic course. "In my view early treatment with antiviral drugs starts the clock ticking too soon, limiting future options and making therapy a necessity for the lifetime of the person," Dr. Levy writes.

One concern is the development of drug- resistant virus. During active HIV replication, the mutations that develop are random, he points out, whereas, mutations that emerge during antiretroviral drug treatment select for viruses resistant to these drugs. Although the argument is made that early treatment can preserve the immune system, he points out that this overlooks the fact that "...these drugs can be toxic and can be directly detrimental to a natural immune response to HIV, which is present in most individuals during the asymptomatic phase of infection."

Recent reports indicate that patients who stop treatment experience a recurrence of viraemia, sometimes at higher levels than before treatment began. "These observations strongly suggest that the immune system has either been compromised by the drugs or 'put to rest' by the therapy." Therefore, once treatment is discontinued, an effective immune response against HIV might not be possible.

Dr. Levy suggests that "...current therapeutic regimens should be reserved for those patients who have symptoms or whose CD4 cell counts have dropped substantially." A better point at which to begin treatment may be when CD4 counts are less than 400 cells per microliter and HIV RNA levels exceed 30,000 copies/mL on at least two occasions. Although these numbers are arbitrary, they are "...representative of what appears to be evidence of an early demise in the immune response, but one that can be reversed."

Dr. Levy also stressed the potential importance of immune restorative therapies, which may be administered in conjunction with antiretroviral drugs. "This approach seems important in light of the fact that current treatments appear to leave the patient in a naive immune state, like an uninfected individuals, rather than someone prepared to control HIV infection."

If viral eradication is not possible, Dr. Levy believes the ultimate objective needs to be " return all HIV-infected people to the state of long- term survivors who do not need treatment even after 20 years of infection."

Source: FASTFAX #195, September 25, 1998 published by We The People Living with AIDS/HIV of the Delaware Valley, Inc. Ref: Lancet 1998; 352:982-983.

It may be added that limited studies suggest antiretroviral treatment of initial HIV-infection may be useful if started within up to 12 months of primary infection, and for those who experience severe seroconversion illness. As Dr Levy reiterates, it remains to be seen if the theoretical benefits of early intervention in “chronic” infection can be practically achieved. Both durability and toxicities of currently available antiretrovirals over the long-term as well as the deleterious effects of medicating an otherwise asymptomatic person have to be considered. There is also the theoretical possibility that host-virus dynamics which may contribute to longer-term non- progression could be destabilised by antiretroviral interventions.

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Glaxo Wellcome Announce Amprenavir Expanded Access Program in the U.S.

Glaxo Wellcome announced 21st September the start of an expanded access program for their experimental protease inhibitor drug amprenavir (formerly 141W94, AgeneraseÒ) expanded access program for both adults and children (>4 yrs) with HIV-infection in the U.S.

A fax from Glaxo to treatment organisations specifies three options for obtaining amprenavir, all of which apply ONLY to people who have received prior treatment with at least one protease inhibitor. : One option will be to enrol in an open- label clinical trial to determine the effect of Agenerase on lipid metabolism (hyperlipidaemia and lipodystrophy) in subjects experiencing these adverse effects and who are not failing current antiretroviral therapy. A second option will be to enrol in an open-label clinical trial which will evaluate Agenerase, or Agenerase together with a second protease inhibitor, in multi-drug regimens for patients who have failed a protease-containing combination. A third option is for patients who are failing their current therapies and need Agenerase to try to create a viable treatment regimen to meet their individual needs.

Regardless of which option physicians and patients opt for, patients need to have received prior treatment with at least one protease inhibitor in addition to fulfilling other standard criteria. Patients will also be strongly encouraged to start at least one other anti-HIV agent that they have not previously used.

U.S. physicians should call 1-800-248-9757 to enrol patients in the early access program. Glaxo contact: Michael Joyner, 919 483-2987

Announcement of access to amprenavir in the U.K. and Europe is still being awaited. The utility of amprenavir in patients pre-treated with protease inhibitors will also need to be more clearly defined to guide choice as to who might benefit from this early access.

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HAART reduces prevalence of cervical HPV lesions in HIV-positive women

Highly active antiretroviral therapy (HAART) in women with HIV infection appears to reduce cervical squamous intra-epithelial lesions (SIL), according to French researchers. This occurs without the clearance of oncogenic human papillomavirus (HPV), they report in the August 20th issue of AIDS.

Dr. Isabelle Heard of the Hopital Broussais in Paris and colleagues evaluated the effects of HAART on SIL in 49 HIV-positive women. "The overall efficacy of the three-drug combination on HIV infection was reflected by an increase in CD4+ cell counts of 62 cells per microliter and a 1.3 log copies/ml decrease in plasma HIV viral load," the investigators report.

The subjects were examined a median of 5 months after receiving a triple-drug regimen that included a protease inhibitor. Dr. Heard's group observed a decreased prevalence of SIL, from 69% to 53%, along with a trend toward reduction in the grade of SIL.

"Among the 13 women who initially presented with high-grade SIL, conversion to lower grade was observed in two women and a full regression to normality was observed in one." Of 21 patients who initially presented with low-grade SIL, nine women had normal cytology findings at follow-up.

However, HPV infection persisted in most cases. Following HAART, the researchers were able to detect the same pre-treatment high-risk viral genotypes in all but one subject.

Based on these findings, Dr. Heard's group believes further studies are warranted to "...substantiate clinical regression of intra- epithelial lesions and to further understand the natural history of HPV infection in HIV seropositive women."

Ref: AIDS 1998;12:1459-1464. Source: CDC HIV/STD/TB Prevention News Update

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Progressive Multifocal Leukoencephalopathy, HIV, and Highly Active Antiretroviral Therapy

Italian scientists report the effect of highly active antiretroviral therapy (HAART) on progressive multifocal leukoencephalopathy in HIV-infected patients with JC virus DNA.

In a letter to the editor of the New England Journal of Medicine, the authors report that among 10 AIDS patients with progressive multifocal leukoencephalopathy who received HAART, neurologic conditions improved in six, remained stable in three, and worsened in one. In response to this report, Colin B. Hall of the University of North Carolina School of Medicine in Chapel Hill and associates--who presented the results of AIDS Clinical Trials Group 243 in the May 7 issue of the journal--agree that HAART appears to help AIDS patients with progressive multifocal leukoencephalopathy. ACTG 243 concluded that neither cytarabine nor therapies of one or two reverse-transcriptase inhibitors alter the path of progressive multifocal leukoencephalopathy in HIV-infected individuals. In their letter, Hall et al. state that "control of HIV should be the aim in HIV- infected patients presenting with progressive multifocal leukoencephalopathy." They also note that trials are currently underway examining agents that may directly reduce JC virus burden.

Ref: Cinque, Paola; Casari, Salvatore; Bertelli, Davide; et al. New England Journal of Medicine (17/09/98) Vol. 339, No. 12, p.848. Source: CDC HIV/STD/TB Prevention News Update

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Sildenafil (Viagra®) Drug Interactions

The recently approved drug, sildenafil citrate (Viagra®), for erectile dysfunction (impotence) should not be used by people who are using organic nitrates in any form, including 'poppers' and certain drugs taken to decrease high blood pressure. Sildenafil can increase the hypotensive (lowering of blood pressure) effects of nitrates which could be fatal. The protease inhibitors and delavirdine (Rescriptor®) will likely increase sildenafil levels while nevirapine (Viramune®) and efavirenz (Sustiva®) will likely decrease sildenafil levels. People taking either a protease inhibitor or delavirdine and are thinking of starting sildenafil should consider using a 25mg dose, since using a higher dose may increase sildenafil's effectiveness and the incidence of side effects. Other drugs commonly used by people with HIV can also affect sildenafil levels. Ketoconazole and itraconazole will likely significantly increase sildenafil levels while rifampin and rifabutin are expected to decrease sildenafil levels in blood. No data exist on any of these interactions yet.

The U.S. package insert states that sildenafil itself is a CYP 450 substrate (mainly 3A4), and is a very weak p450 inhibitor (several isoforms). The clinical significance of its inhibition of p450 on any other co-administered drugs (especially protease inhibitors) is unknown but thought likely to be insignificant.

Source: Adapted from an article in PI Perspective 25, September 1998. "From Project Inform, for more information contact the Project Inform National HIV/AIDS Treatment Hotline, 800-822- 7422."

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Atorvastatin and Gemfibrozil for Protease-Inhibitor-Related Lipid Abnormalities

Scientists from Minnesota report the treatment of HIV-positive patients with both protease inhibitors and the lipid-reducing agents gemfibrozil and/or atorvastatin. Of 133 patients receiving protease inhibitors, those who took saquinavir and ritonavir were significantly more likely to have raised lipid concentrations meeting intervention criteria as outlined by the U.S. National Cholesterol Education Program (NCEP). Forty-four patients were enrolled in intervention programs. Twenty patients with lower increased lipid concentrations were started on exercise and diet programs, while the others were given gemfibrozil and/or atorvastatin. Twelve of the exercise and diet program patients were judged treatment failures and started on the lipid-lowering agents. Of those on gemfibrozil alone, 19 had sub-optimum responses and had atorvastatin added to their regimen. Patients who received both medications showed decreases in their lipid levels, with triglyceride concentration falling 60 percent over six months and mean cholesterol concentration declining 30 percent. The authors note that NCEP guidelines advise using caution in the combination of statins and gemfibrozil since there is a concern for increased risk of myopathy. There may also be increased toxicity when atorvastatin is used with cytochrome p450- interfering medications, such as protease inhibitors. However, the researchers observed no instances of myopathy, raised creatine kinase of liver enzymes, or adverse virologic effects, and they suggest that raised lipid concentrations in HIV-infected patients on protease inhibitors can be managed by following NCEP guidelines.

Ref: Henry, Keith; Melroe, Holly; Huebesch, Jacquelyn; et al. Lancet (09/26/98) Vol. 352, No. 9133, p.1031. Source: CDC HIV/STD/TB Prevention News Update

Additionally Hewitt and colleagues reported at ICAAC on 9 patients with very high triglyceride levels on PIs (716 to 2,847 mg/dl, normal being less than 150). Virtually all of them had a decrease in their triglyceride levels on 600 mg of gemfibrozil twice a day; however, the majority had high cholesterols that did not appreciably decline. In 3 patients who subsequently changed PIs (from indinavir to nelfinavir), triglyceride levels rose again, and rebounding was seen when patients discontinued gemfibrozil use. No adverse reactions were reported. In patients with hypertriglyceridaemia on PIs, gemfibrozil seems to be safe and well-tolerated, but larger studies are needed to assess long term efficacy in chronic and changing regimens and other treatments will be needed to treat the common occurrence of elevated cholesterol in persons living with HIV.

Ref: Abstract I-88 Coverage provided by Kenneth Mayer, M.D. Source: The Body.

It should be an urgent priority to more clearly define the raised triglyceride and cholesterol levels currently being observed amongst people with HIV. Their association to body shape changes and lipodystrophy as well as increased risk of cardiovascular events or pancreatitis needs further determination. It is unclear if the maximal efficacy of pharmacological agents in lowering triglyceride levels (around 50%) will translate to any degree of clinical benefit.

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