NATAP REPORTS
January 1998 Volume 1, Number 3-4, Section 9

Conference Briefs
     Six Drug Salvage Therapy
    In vitro Effect of Protease Inhibitors on Methadone
    Effect of Flu Vaccine on Viral Load
    T-20 (Fusion Inhibitor)
    PMEA
    MKC-442
    D4T/3TC and AZT/3TC
    Pediatric Studies

Salvage Therapy with 6 Drugs. Dr. Cassy Workman of Australia presented this abstract in Hamburg saying that because many individuals have failed protease inhibitor therapy salvage therapies need to be identified. A strategy is to recycle nucleosides for individuals who have been heavily pretreated with all available nucleosides. This study explores that concept for 12 heavily pretreated individuals who have failed previous treatment regimens. Following is preliminary 12 week data.

All 12 individuals had been exposed to and failed regimens including all available nucleosides and 3 protease inhibitors (indinavir, ritonavir and saquinavir). The 12 were started on an open-label combination of 6 drugs:

    1. d4T 40 mh bid
    2. 3TC 150 mg bid
    3. ddI 400 mg per day
    4. nevirapine 200 mg bid
    5. nelfinavir 1000 mg tid
    6. saquinavir HGC 600 mg tid (old formulation of saquinavir)

D4T, 3TC, ddI and saquinavir were recycled for all 12 individuals. All 12 were naive to nevirapine and nelfinavir. The mean baseline viral load was 364,877 copies/ml and the median was 41,787 copies/ml. The range was 1,200 to 2,487,483 copies/ml.

9 patients remained on all 6 drugs and reached undetectable by week 12. The patients need to continue to be followed because 12 weeks is not long enough to conclude this approach worked for them. 3 who had been intolerant to components previously were again intolerant and are marked below. Compliance data were recorded. See Table 25.

Table 25. 6 Drug Salvage Therapy: Results

*These were the 3 individuals who were intolerant to components of the regimen.

The author concluded that prior protease inhibitor experience may have caused some cross-resistance to nelfinavir, and considering that resistance to nevirapine can develop quickly, the results are surprising. They suggest that recycling may be effective if enough agents are used. This approach should be explored with further study. Failure in this group was not correlated with non-compliance but with inability to tolerate all drugs in the regimen.

In Vitro Effect of HIV Protease Inhibitors on Methadone Metabolism.  When taken together methadone and a protease inhibitor can cause a drug interaction. Methadone is eliminated by P4503A4. Protease inhibitors and NNRTIs are eliminated through the same liver process. Healthy liver microsomes were used for this study. To predict the clinical relevance of the inhibitory effect of the protease inhibitor on methadone pharmacokinetics, Ki were compared to mean plasma concentrations of protease inhibitor measured in HIV-infected individuals after administration of standard doses. Assuming that the same concentrations are present in the hepatocytes, a 2-fold increase in methadone AUC can be expected when co-administered with ritonavir; coadministration with indinavir should lead to a 30% increase in methadone AUC, and no interaction is expected with saquinavir. Authors said a human study should be conducted to validate this data.

Impact of HIV Protease Inhibitors on HCV Viremia. The authors of this study said, co-infection with HIV and HCV is associated with increased HCV RNA. However, the authors of abstract I-167 said, some studies have suggested that chronic hepatitis C could be more severe in HIV infected individuals and others have failed to find evidence to support this hypothesis.

The aim of this study was to explore the effect of protease therapy on HCV viremia. 19 IVDUs coinfected with HIV and HCV were prospectively followed. All had progressive HIV and were treated with a protease inhibitor (ritonavir-9, indinavir-7, ritonavir+saquinavir-3) and 2nucleosides.HIVRNA (Roche Amplicor), CD4, CD8, and HCV RNA were measured at baseline and weeks 6, 17, and 32.

Authors concluded that although there was an initial increase in HCV viremia noted at week 6, there was little change in HCV viremia in subsequent follow-up to 32 weeks. Authors noted there was no decrease on HCV viremia despite theimprovement of immune functions.See Table 26.

Table 26. On HCV viremia despite the improvement of immune functions.

Baseline and changes in HCV and HIV RNA are expressed in log. 5.3 log is about 199,000 copies/ml; 5.0 log is 100,000 copies/ml.

Effect of Infuenza Vaccination on HIV RNA. 25 HIV-infected individuals were randomized to receive the Connaught whole virion influenza vaccine (n=9), the Connaught subvirion influenza vaccine (n=10), or a saline control (n=6). The baseline median CD4 count was 162 cells (range 1-788); the median viral load was 1750 copies/ml by RT-PCR (range 20-191,600). All but 4 individuals were receiving antiretroviral therapy. Viral load was determined at 1, 2, 5, 7, 14, 21, 28 and 60 days.

Results. The influenza vaccine was associated with a >3 fold increase in plasma viral load in 42% (8) of the vaccinated individuals. The increase was transient, occurred at a median of 21 days, and was of "limited magnitude" (maximum 8-fold increase over baseline). 5 of the individuals with a rise in viral load received the subvirion flu vaccine and 3 received the whole virion flu vaccine. 7/19 vaccinated individuals had a >4 fold increase in antibody titer to the flu vaccine. Investigators reported there was a positive association between response to flu vaccine and rise in viral load. Viral load increases occurred even in persons on regimens containing a protease inhibitor. Authors said, the clinical significance of the "burst" in viral load during immune stimulation requires further investigation.

T-20. At the September ‘97 IDSA meeting, preliminary data was reported from a phase I/II dose escalating study of T-20. T-20 inhibits fusion of HIV with host cells (CD4s). Although the following data is encouraging, it is preliminary from early stages of research in human. As well, current administration of T-20 is through an IV. Further studies are needed to evaluate T-20’s efficacy and safety. Fusion inhibition’s approach to HIV therapy is different than any other currently approved HIV antiviral.

16 treatment-naive or experienced (off drugs for 15 days prior to starting T-20) individuals received doses of 3, 10, 30 or 100 mg of T-20 every 12 hours for 14 days.

T-20 was administered by bolus intravenous infusion.

Investigators reported no drug-associated adverse events and a dose dependent decrease in plasma viral load and increase in CD4. The investigators concluded they saw significant anti-HIV activity. See Table 27.

Table 27. T-20 - DOSE Mean Viral Load Mean CD4

All 4 participants receiving the 100 mg dose were <500 copies/ml (undetectable).

Follow-up studies are necessary to confirm preliminary findings. Sub-cutaneous administration with an implant is expected to be explored in a forthcoming study. Hopefully, the company can develop an alternative way to administer T-20, otherwise it may only be acceptable for individuals with no other treatment options.

Adefovir Dipivoxil (PMEA). The NATAP Reports July issue contains a lengthy article about this nucleotide. At this point the information and data available for PMEA are preliminary, based on a small number of individuals. But the limited data so far suggests: (1) viral load reductions of about 0.5 log; (2) the potential appeal for PMEA is that it may have limited cross-resistance with nucleosides, so if you’ve had extensive nucleoside experience PMEA may still be effective; (3) the limited data suggests that resistance and consequent diminished antiviral effectiveness may not develop very easily. Additional data is expected in February 1998 from study #408, which may be revealing in how PMEA may be helpful.

MKC-442. MKC-442 is a new NNRTI in an earlier stage of development by Triangle Pharmacueticals. The company has been conducting a dose ranging study of 48 HIV infected individuals. Previously, they reported a median decrease in viral load of 1.18 log after 8 days for those taking 500 mg bid. In Hamburg, they reported median reductions of -1.41 log and-1.30 log at 8 and 15 days, respectively. After 1 week, those on 750 mg bid had their dose raised to 1000 mg bid for 3 additional weeks. The results from the 1000 mg dose are not yet available. Preliminary pharmacokinetics predicts a half-life of 6-8 hours for MKC-442. But, the company is also experimenting with a dose of 500 mg Tid which might be useful for individuals with a shorter half-life than 6-8 hours who thereby might have a lower trough. Clinical trials have recently started using a dose of 750 mg bid. When resistance develops from drug failure they have observed a key mutation at 103; K103N is also a key mutation for DMP-266. Investi-gators reported the drug as well tolerated with 10/44 experiencing headache, 5/55 nausea/vomiting, 2/44 experiencing a mild grade 2 rash, and modest elevations in GGT which is a liver related lab measure.

D4T/3TC and AZT/3TC. The sequencing of nucleoside combinations has become an issue now that data from a number of studies released in the past year have shown that several 2 drug nucleoside combinations (AZT/3TC, d4T/3TC, d4T/ddI, AZT/ddC) may be reasonable choices for use in an individual’s first line therapy, which could be a 3 or 4-drug regimen including a protease inhibitor(s). Sequencing may depend on resistance and cross-resistance between nucleosides. See enclosed Resistance Supplement for a discussion of this subject.

Preliminary data from several studies have suggested that d4T/3TC is equivalent to AZT/3TC in treatment naive individuals, in terms of CD4 and viral load responses. In Hamburg, interim data from two studies were reported suggesting that for treatment naive individuals d4T+ddI or d4T+3TC in combination with indinavir appear to be as efficacious as AZT+3TC in combination with indinavir. Dr. Trip Gulick reported 6 month data from an interim analysis comparing d4T+3TC+ indinavir to AZT/3TC+indinavir. About 44 individuals were randomized to each arm in this open label study. At week 12, the number of evaluable patients was almost as large as the number starting the study and changes in viral load and CD4 were about equal for both groups. At month 6, the number of evaluable patients was only 15 and the d4T group CD4 increase was greater for the d4T group than for the AZT group. But it is too soon to say if there was a true difference in CD4.

Dr Robert Murphy reported 6 month data from an interim analysis comparing d4T/ddI+indinavir to AZT/3TC+indinavir. About 45 individuals were randomized to each of the two arms in this open label study. As was reported by Dr. Gulick at 12 weeks, where the number of evaluable patients was almost equal to the the starting number, there was no difference between the two groups with regards to CD4 or viral load. At week 24, there was a trend towards a higher CD4 increase in the d4T group (350 CD4 increase in the d4T group vs about 75 CD4 increase in the AZT group); but, the number of evaluable patients was only 10 in each arm and too small to draw a conclusion. Both Drs Gulick and Murphy said that based on this interim analysis d4T/ddI and d4T/3TC appeared about equivalent to AZT/3TC in terms of efficacy. But, both cautioned this is an interim analysis and follow-up data may be more revealing. An ultrasensitive viral load test will be used in follow-up analysis. When deciding which nucleoside combination to select, its resistance implications should also be considered. See the Resistance Supplement in this issue.

Protease Inhibitors & Pediatrics

Therapeutic options for children are more limited than for adults. The pathogenesis or course of disease for children is different than for adults. Children born with HIV do not have a developed immune system to fight HIV. An adult has a developed and intact immune system when HIV is contracted. Therefore, the disease can progress quickly in children. It may be more crucial for children to initiate therapy earlier in the course of disease progression than for adults. Although not yet widely accepted, some experts counsel that a potent therapy capable of maximal suppression of viral load should be considered as soon as possible after HIV infection.

SGC Saquinavir+Nucleosides. Fourteen children from 3-13 yrs old who were able to swallow adult capsules started treatment with SGC SQV (initial dose, 33 mg/kg tid) and 2 nucleosides of choice. Because a child’s organ system is not fully developed and constantly quickly evolving the pharmacokinetics (blood levels) of a drug become more of a concern than for an adult. Selecting adequate dosing for children is more complicated and difficult. Dosing of any HIV drug may need to be more individually assessed than for adults.

The study is assessing tolerability, efficacy, and pharmacokinetics. Participants will be followed for a minimum of 24 weeks with intensive pharmacokinetic (PK) sampling at week 0 (single dose profile), week 4 (steady state), and as necessary thereafter. Sparse PK sampling is scheduled at every study visit after week 4.

12/14 children had prior nucleoside experience with a mean duration of 4 years. The nucleoside combinations selected for this study were: d4T/3TC (11), d4T/ddI (2), or AZT/3TC (1).

Safety and tolerability. No serious adverse events have been reported. 1 child with pre-existing thrombocytopenia had a marked decrease in platelet count study week 4. There was no interruption or discontinuation of therapy.

Preliminary results. The mean baseline CD4 and viral load were 446 cells and 4.6 log (about 39,000 copies/ml.) Because of the different course of disease progression in children compared to adults, the CD4 and viral levels have a different significance. Investigators reported by week 4, CD4 increased by 95 cells, and mean viral load declined by 2.1 log. At weeks 4 and 8, 5/12 and 7/7 children were <400 copies/ml. By visual observation of the line graphs it appeared that viral load at week 8 for 6/8 children was steady or declining further compared to the week 4 reduction. One child’s viral load reduction was about 1 log at week 4 and the same at week 8. One child who had been on study medications for 12 weeks had sustained about a 2.2 log reduction at week 12.

The authors concluded the PK characteristics are consistent with expectations. And the drugs were generally well tolerated.

Indinavir PK in Children. At the 8th European Congress of Clinical Microbiology and Infectious Diseases in May ‘97, Courtney Fletcher from the University of Minnesota, PhD, reported findings from evaluating indinavir pharmacokinetics (PK) in HIV-infected children receiving indinavir with ddI+d4T. Indinavir penetrated the CSF in 4 children measured with concentrations of 151-977 ng/mL.

In their PK evaluation of 12 children taking indinavir+ddI/d4T indinavir doses were adjusted if trough concentrations were <100 ng/mL. 9/12 children required adjustment of their indinavir regimen to q6h as trough values were <100 ng/mL. Investigators concluded indinavir PK in these children were highly variable. With a regimen of 500 mg/m2 q8h, 9/12 children had trough values <100 ng/mL. Fletcher said concentrated guided dosing of indinavir may be necessary for an optimal anti-HIV effect, and can be used since intraindividual variability was modest.

Ritonavir + Nucleosides. At ICAAC, 12 weeks data were reported for a randomized open-label study (ACTG 338) comparing AZT/3TC, d4T+ritonavir, and AZT/3TC+ritonavir. 298 children enrolled had a median age of 7.1 years (range 2-17 yrs), baseline viral load of 4.32 log (21,000 copies/ml). An interim analysis at week 12 showed for those in the AZT/3TC arm 6/43 (14%) were <500 copies/ml. Children in both ritonavir containing arms achieved about 60% undetectable (500 copies/ml.) At week 12, of those children on a ritonavir containing regimen 57% were on full dose ritonavir, and 10% permanently discontinued ritonavir. Those not responding well to AZT/3TC (viral load>10.000 copies/ml) were offered ritonavir+d4T+nevirapine. At week 24, the Data Safety Monitoring Board examined safety data and did not detect any safety problems for those taking ritonavir. The important messages are that no safety concerns were detected at week 24; and if a child is taking nucleoside therapy, switching to a protease inhibitor combination should be considered; switching to AZT/3TC was inferior to the two ritonavir regimens. The study is ongoing and 48 week data will be reported this Summer.

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