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3rd International Workshop on HIV Drug Resistance & Treatment StrategiesJune 23 - 26, San Diego, CA. |
Medical Consultant
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June 23 - 26, San Diego, CA. |
Tipranavir active in vitro against multiple PI resistant HIV
The non-peptidomimetic PI Tipranavir, has demonstrated in vivo activity against HIV-1. Screening of activity against clinical isolates resistant to multiple PIs generally revealed maintenance of tipranavir activity 1,2. At Virco 3, only 3/107 clinical isolates resistant to approved PIs were resistant (>10-fold change in tipranavir sensitivity) and 8/107 tested isolates were of intermediate resistant (4-10-fold). Virus resistant to single PI were all sensitive to tipranavir with SVQ resistant virus demonstrating a 2.5-fold hypersensitivity to TPV. Mutations with hypersensitivity had 48V or 82A, whereas the typical genotypic patterns in the few resistant samples had 82T, often with 84V, (or in some cases 84V/90M although resistance was dependent on background mutants) plus multiple secondary mutations.
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"The data clearly suggest that tipranavir's unique design as a non-peptidic protease inhibitor may provide new hope for patients struggling with drug resistance, especially among protease inhibitors," said Dr. Larder. "Since considerable numbers of patients failing HAART harbour PI-resistant strains of the virus, the development of new agents active against these variants is an urgent priority."
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Two abstracts addressed preliminary results from an on-going, blinded study comparing ABT378 400mg + either 100 or 200mg RTV bid in 70 persons experienced on 1 PI but na•ve to NNRTIs 1,2. Patients with viral load between 1000 and 100,000 and >3 months PI exposure were given 2 weeks ABT-378/r on their original NA backbone then the NA backbone switched and Nevirapine added. At baseline median VL was 4.0log and CD4 380/mm3 with 64% >4-fold resistant to the previous PI and 33% resistant to >3 PI. After 2 weeks the mean VL had fallen ~1log with 94% experiencing a >0.5log drop in VL. At week 24, 84% of patients were <400 copies by OT and 77% by ITT analysis. Less than 50 data were not available. Baseline phenotypes were not predictive of response at week 24 although rebound appeared more likely in persons with resistance to >2 of their new drugs at baseline. Genotype data on rebounding virus was also unavailable. Non-fasting lipid data indicated 23% of patients had triglycerides >750mg/dl and 24% cholesterol >300mg/dl, lipid abnormalities being most common in those with lipid abnormalities at baseline.
The lack of a standard of current care arm makes interpretation of these data difficult, especially given 67% of patients remained sensitive to at least one approved PI at baseline.
A separate presentation studied the genotypic resistance produced by passage of ABT378/rtv (in 5:1and 15:1 ratios). Patterns of 84V plus 46I/10F and 50V/46I were found to be selected. RTV did not appear to influence selection. These data suggest ABT378 failures are likely to have broad PI cross-resistance 3.
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These data assessed 70 patients who had only ever received d4T based 2 and 3 drug regimens 1. ZDV mutations including at codons 41, 210, and 215 were found in 4%, a further 6% had ZDV mutations at baseline and accumulated further ZDV mutations on d4T and 1 patient developed an MDR pattern (Q151M) on therapy. Similarly, in both children and adults treated with only d4T based regimens 2, 47% of 34 patients had ZDV mutations, mostly at codon 215. ZDV experienced patients, in this composite analysis of several studies, tended to develop more ZDV type mutations on d4T. In this study, the presence of ZDV mutations was not associated with therapy failure on d4T.
In the Albi study of d4T/ddI therapy 3, 15/24 developed ZDV phenotypic resistance, 12/24 3TC resistance (but no 184V mutations), 4/24 ddI resistance and 3/24 ABC resistance. 215Y and 41L were the most common mutations observed.
These data support the view that d4T may select ZDV type mutations, or more correctly thymidine analogue mutations, but suggest that this is a relatively infrequent event.
Similarly, ZDV mutations were noted to impact the virological response to subsequent d4t/3TC or ddI/HU therapy 4.
References
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Several mechanisms of multi-nucleoside resistance have been reported, the Q151M being the most commonly reported variant. This was reported in 3.5% of mostly heavily pre-treated patients from one clinic, commonly in association with multiple ZDV mutations plus M184V and NNRTI mutations. A further 0.5% of tested patients in this cohort had the 69SS MDR pattern, all (2) patients having only received ZDV based therapies 1. Passaging of an archived sample derived from a patient who developed Q151M on therapy with single NAs, indicated that Q151M evolved under selection pressure from either ZDV, d4T, ddI or ddC 2. This suggests that characteristics of HIV pre-therapy may predetermine the resistance pattern, which then evolves during NA therapy. These viruses appear to maintain phenotypic sensitivity to adefovir 3.
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Given that the days of dual NA's are over, does this tell us anything about which NA's should be combined in HAART? |
This study examining the impact of prior nucleosides and baseline resistance on responses to New NNRTIs plus either NFV, EFV or both in ACTG 364 found several significant correlation's. Patients entering having received ZDV/3TC vs. ZDV/ddC were more likely to have not only 184V but also different ZDV mutations such as 70R and 219Q. The ZDV + ddI/ddC recipients more commonly had 210 and 215. ZDV/3TC recipients were also more likely to have greater than 5 RT mutations (not supporting the fidelity hypothesis). In 'early failures' (VL>2000 at week 16) indicated a significant association with prior ZDV/3TC use. In late failures (VL <500 at week 16, >500 in weeks 20-48) association was found with the number of baseline RT mutations. This supports the view that ZDV/3TC may limit future treatment options more than other ZDV regimens.
Ref: Katzenstein D, Bosch R, Shafer R et al. Virological response to nelfinavir, efavirenz, or both in patients with >4 years of previous nucleoside RT inhibitors in ACTG 364. Abstract 67. Antiviral Ther 1999;4(suppl 1):6.
Data from CNA3003, indicate that viral rebound on ZDV/3TC/ABC was mostly with the 184V mutation alone although occasional samples had ZDV or ABC mutations in addition 1. The authors concluded that ZDV/ABC could be included in subsequent therapy if 184V alone breakthrough occurred.
Further analysis of pooled data from abacavir studies, supported that this agent remains active in the presence of M184V alone 2. In persons entering studies with wt, 184V alone, 2NRTI mutations excluding 184V and >3NRTI mutations virological responses of <400 copies were observed in 53%, 66%, 33% and 17% respectively.
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This limited data suggests that ABC triple NA based combos will be salvageable with further NA based regimens. However, this is with "early" failure, greater numbers of resistance mutations would be expected to accumulate with ongoing replication in the face of continued drug pressure. Later, or more numerous genotypic changes may not be as forgiving. This again emphasises the need for regular VL monitoring and early switch on first signs of confirmed virological failure. |
Final results of both Viradapt and GART were reported at this meeting 1,2.
For Viradapt, after 6 months all patients were able to access genotyping between month 6 and 9. Study rules were provided to physicians to enable result interpretation. Viral load results are shown in the table below:
| (OT) | Log Drop% | <200 copies/ml | ||
| Geno. | No Geno. | Geno. | No Geno. | |
| 3 months | 1.0 | 0.46 | 29% | 14% |
| 6 months | 1.15 | 0.67 | 32.3% | 14% |
| 9 months | 1.15 | 0.86 | 31.3% | 12.5% |
| 12 months | 1.15 | 0.98 | 30.4% | 30.5% |
Greatest viral load reductions at week 24 were seen in persons who received genotype at baseline and a wild type protease gene. Poorer responses were seen in persons with PI mutation at either codons 46, 48, 82 and 90. Plasma concentration of PI was also associated with improved chance of response 3. Although no specific adherence measures were included and patients were not asked the timing of their previous dose in the PK sub-study, up to one third of patients had 'low' plasma levels (using a calculated estimate from in vitro data). A poster discussing the costs of genotyping in Viradapt (estimated at $500/test) suggested the cost was largely offset by reduced drug usage 4.
In GART more short-term benefits were seen. Average week 4-8 viral load drop was -1.19 vs. -0.61log for GART vs. no GART groups. Absolute viral load benefit was maintained at 0.44log to week 12 but significance in the % undetectable was lost by week 12. No significant impact of baseline CD4, VL or number of previous PI received were observed in subgroup analyses (i.e. GART continued to show advantage). The average estimated log reduction per 'active' drug in the new regimen was 0.37log with reduction per active drug being 0.10, 0.59, 1.04 and 1.59 for 1, 2, 3, and 4 drugs, respectively. Mutations 69D in RT and 90M in PI were associated with poorer treatment responses and 30N in PI with a more favourable response 5.
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Drug exposure/selective pressure and viral fitness may interplay in the process of evolution of PI resistance. For example both RTV and IDV have 82A as a signature mutation. This mutation alone showed fitness advantage in the presence of low concentrations of RTV but not IDV. Advantage with IDV was only observed with >1 additional mutation in protease and fitness advantage relative to wild type virus only demonstrated in a narrow range of IDV concentrations. This may explain in part wild type rebound on IDV as at many IDV concentrations little viral advantage is gained by genotypic variation. For SQV mutations, L90M showed fitness advantage at low concentrations and M48V at high concentrations. This provides an explanations for differences in mutant frequencies between SQV formulations. Given the unfavourable cross resistance with L90M (see below) it underlines the importance of achieving a high SQV selective pressure.
Ref: Mammano F, Trouplin V, Clavel F. Integrated analysis of resistance and fitness in HIV protease inhibitor resistance evolution pathways. Abstract 46. Antiviral Ther 1999;4(suppl 1):6.
In the Merck 075 study 1 examining response to an indinavir (plus efavirenz plus adefovir) regimen in NFV failures, L90M was also associated with poor response to the new regimen and D30N with a better response (a 10-fold difference in time to regimen failure). These and other data suggest L90M is a PI multi-resistant genotype. However, in this study the intriguing question is raised as to why NFV selected D30N in some patients and L90M in others. If exposure issues are important in viral selection patterns, it may have been that poor NFV exposures selected L90M and that these patients, for adherence or metabolic reasons, may have then gained poor IDV exposures. (i.e. the reason they got L90M may be more important than the mutation itself).
However, in a similar ACTG study (ACTG 372) using efavirenz, adefovir and nelfinavir in PI experienced patients L90M and to a lesser extent mutant codons 77 and 10 were associated with poorer treatment responses 2. In this study, as with GART, the more 'active' drugs in the regimen, the better the response.
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Several studies examining the prevalence of key mutations in RT and protease genes in recent seroconverters of persons presenting for care suggested a concerning prevalence of both ZDV, possible NNRTI mutations and less commonly PI resistance. Data from DuPont, however, suggested that despite up to 20% of patients entering Efavirenz studies with NNRTI polymorphisms, few (only 1.9% of participants) showed evidence of phenotypic resistance to EFV 1. However, sequencing of NNRTIs appears unfeasible, the response to EFV in NNRTI-experienced patients entering the EFV EAP being generally poor, even if only Y181C was the dominant mutant 2. This not surprising given that of patients in another study failing NVP, 73% and 70% of isolates showed resistance to DLV and EFV, respectively, by the Vircogen assay 3.
The various studies of na•ve patients used different methodology to define resistance, both phenotypic and genotypic 4. In general, phenotypic assessments gave the lower incidence. However, overall intermediate (4-10-fold) and resistant ).10-fold) resistance was seen in 1-7 % of NA, 1-18% for NNRTI and 1-11% for PI. Incidence of resistance was higher in patients with recent known seroconversion dates, reflecting the probable decay to undetectable levels of mutant virus with time.
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Limited information was included in the meeting on non-viral means of drug resistance. However, this abstract on P-glycoprotein, reported data on expression of Pgp in 18 HIV+ persons on reverse transcriptase plus single or dual PI therapy. Plasma levels of PI were reported to be in the 'therapeutic range' in both patients with viral control and viral rebound. Expression of Pgp in peripheral PBMCs , was observed in 33% of CD4+ cells, with test for activity of Pgp indication this expression was of active/functional enzyme. No relationship with virological status was reported.
Ref: Bossi PH, Legrand O, Faussat AM, et al. Expression and function of P-glycoprotein in HIV-1-infected patients receiving protease inhibitor. Abstract 27. Antiviral Ther 1999;4(suppl 1):21.
HIV integrase represents a unique viral target. Deleting of the integrase gene leads to viral DNA production but this DNA remains circularised adjacent to the nucleus. Assembly of integrase with the viral DNA to form a complex, processing of 3' end of the viral DNA strand in preparation for integration and stand transfer (joining viral to host DNA) of the viral DNA, the functions of integrase are then not performed. Daria Hazuda from Merck reported activity of two chemical classes which act as competitive strand transfer to block integrase. The IC50 is 0.1-0.2(M for these inhibitors. Selection experiments demonstrate resistance to these compounds can occur, the resistant viruses showing consistent mutation patterns and good fitness. Sensitivity changes were in the 3-10-fold range. Higher levels of resistance were seen with dual mutants. Mutations lie adjacent to the catalytic residues. The compound, however, remain in phase 0 due to on-going synthesis work aimed at reducing protein binding and improving pharmacological properties.
Ref: Hazuda DJ. Inhibitors of HIV integrase: antiviral activity and mechanism. Abstract 1. Antiviral Ther 1999;4(suppl 1):3.
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TREATMENT ALERT
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In July 1998, Abbott Laboratories were forced to withdraw ritonavir capsules world wide due to the discovery of a new crystalline form of the active component with differing formulation properties. Ritonavir liquid formulation was, fortunately, not affected and could be substituted for the capsules in most patients. The ritonavir liquid had proved problematic to many on this drug due to its intensely disagreeable taste and is inconvenient to travel with or dose in public.
Since 1998, efforts were made to create a capsule formulation able to effectively deliver the new crystalline (form II) ritonavir and in January a product license application for the new soft elastic capsule (SEC) was submitted to the European Medicines Evaluation Agency (EMEA) for European Approval.
Prior to receiving full marketing approval Abbott Laboratories (UK) are now in a position to supply the ritonavir SEC in the UK on a named patient basis following physician request to the company.
Additionally Abbott have announced U.S. Food and Drug Administration (FDA) approval for ritonavir soft-gelatine capsules Norvir" in the U.S.
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This announcement will be welcomed by those patients who have suffered the liquid formulation and to whom ritonavir is an indispensable component of their combination therapy. The new capsules have a similar alcohol content to both the old capsules and the ritonavir liquid formulation. They are in a sealed "rugby ball" shaped capsule, but are smaller than the similarly shaped saquinavir-sgc or amprenavir capsules. Ritonavir SEC should be refrigerated at 2-8 degrees centigrade prior to dispensing where they have a shelf life of one year, and have a shelf life of up to one month out of the fridge (at less than 25 C). It is recommended that bottles of ritonavir SEC bottles are refrigerated until needed then single bottles may be kept unrefrigerated while being used. each bottle. Supplies on a named patient basis will be dispensed 2 months at a time. Physicians should contact the named patient administrator on 01628 644370 for further information or to register patients. |
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OTHER NEWS
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French researchers examined the efficacy of genotypic resistance-analysis when creating medication therapy for patients with drug-resistant HIV-1. Patients were similar in risk factors, age, sex, previous treatment, CD4-cell count, and HIV-1 viral load. Forty-three of the patients received treatment according to standard guidelines, while 65 received treatment according to genotyping. In month three, the mean change in HIV-1 RNA was -1.04 log in the genotyping group, compared to -0.46 log in the standard treatment group. By month six, the changes were -1.05 log copies/mL in the genotype group, compared to -0.67 log copies/mL in the control group. Investigators noted that by month three, 29 percent of patients in the control group had undetectable levels of HIV-1 RNA, compared to 14 percent in the standard treatment group. After six months of treatment, 32 percent of the genotyping group had undetectable levels of HIV-1 RNA, as compared to 14 percent for the control group. The researchers conclude that genotypic resistance profiling can be beneficial when choosing therapeutic alternatives for drug-resistant HIV. Further study of genotypic resistance testing for clinical decision-making is suggested.
Ref: Durant, J.; Clevenbergh, P.; Halfon, P.; et al. Lancet (26/06/99) Vol. 353, No. 9171, P. 2195; Source: CDC HIV/STD/TB Prevention News Update
Australian researchers investigated the natural course of lipodystrophy associated with long-term therapy for HIV-1 infection that includes a protease inhibitor. The condition was measured by questionnaire, physical exams, and dual-energy x-ray absorptiometry. The study, which involved 113 patients who were taking HIV-1 protease inhibitors and 45 HIV-1 patients never treated with a protease inhibitor, found a 98 percent concordance between patients' reports of the presence or absence of lipodystrophy and physical exam. According to the researchers, weight prior to therapy, fasting triglyceride, and C-peptide concentrations early in treatment, and therapy length appear to be predictors of the severity of lipodystrophy. While the condition was common and progressive following nearly two years of treatment with protease inhibitors, it was not generally severe. Other common conditions were hyperlipidaemia and impaired glucose tolerance.
Ref: Carr, Andrew; Samaras, Katherine; Thorisdottir, Anna; et al. Lancet (19/06/99) Vol. 353, No. 9170, P. 2093. Source: CDC HIV/STD/TB Prevention News Update
Scottish researchers studying uptake of antenatal HIV testing report most women surveyed thought that routine HIV screening should be performed during pregnancy. Of the 924 studied, about 88 percent were tested for HIV and one woman already known to be infected was, thus, not tested again. The prevalence of HIV infection was 0.2 percent of 817 women. The two most common reasons offered for rejecting the test were, "Not necessary as I've no chance of being positive" and "I've been in a stable relationship for a long time." The researchers note that, compared to new data, the uptake rate in the 1996-1997 opt-in study was only about 35 percent. While changing attitudes toward HIV testing may play a role in the increased rate, the authors suggest "that this approach [in which testing was routine unless a woman declined] is more effective than an opt-in approach, and those who decline testing do not seem to be doing so because of high risk status."
Ref: Simpson, Wendy M.; Johnstone, Frank D.; Goldberg, David J.; et al. British Medical Journal (19/06/99) Vol. 318, No. 7199, P. 1660. Source: CDC HIV/STD/TB Prevention News Update
Universal, voluntary antenatal HIV screening is a cost-effective intervention that should be adopted in the London area, conclude researchers from the Netherlands and the United Kingdom. A cost analysis found that the estimated direct lifetime medical and social care costs of childhood HIV infection totalled 178,000 pounds, with a 5 percent discount rate for time preference. The net cost of testing pregnant women for HIV in areas where prevalence is high was less than 4,000 pounds per life year gained, while the cost effectiveness would be under 20,000 pounds per life year gained in areas with relatively low prevalence rates. The researchers recommend implementation of universal, voluntary antenatal HIV screening in London and "serious consideration" of the policy in other areas of the country, based on local prevalence and the expense of testing.
Ref: Postma, M.J.; Beck, E.J.; Mandalia, S.; et al. British Medical Journal (19/06/99) Vol. 318, No. 7199, P. 1656. Source: CDC HIV/STD/TB Prevention News Update
Potential adverse interactions between sildenafil (Viagra) and antiretroviral drugs for HIV infection have been previously reported. Now, the case of an HIV-infected patient who died while receiving sildenafil and 2 protease inhibitors is described in the June 12th issue of the Lancet.
The patient, a 47-year-old man with no history of chest pain, was diagnosed with HIV-1 infection in 1995, Drs. Mark C. S. Hall and S. Ahmad of the Royal Bolton Hospital in the UK report. For more than 1 year, he had been receiving highly active antiretroviral therapy (HAART), which included ritonavir and saquinavir.
The patient was prescribed sildenafil at 25 mg to treat erectile dysfunction of no known cause. No adverse effects occurred after use on 8 occasions. However, he developed chest pain after the ninth dose.
Upon presentation, the patient was normotensive and his pulse was 92. No clinical signs of ventricular failure were observed. "An electrocardiogram (ECG) showed an extensive anterolateral myocardial infarction, with 2-4 mm ST segment elevation in leads V1-V6, and aVL," Drs. Hall and Ahmad write. The patient had no history of nitrate drug use, hypertension, diabetes, or family history of ischaemic heart disease. However, he had a 30-year history of smoking and currently smoked 30 cigarettes per day.
Twenty-four hours later, the patient began to deteriorate and developed hypotension and evidence of pulmonary oedema. "Echocardiography indicated an akinetic left-ventricular anterior wall, septum, apex, and lateral wall, with a subjective ejection fraction of 20-30%."
Some improvement was seen following diuretic therapy, inotropic support, and non-invasive continuous positive-airway-pressure ventilation, but the patient soon became more hypotensive and hypoxaemic. Despite intubation and ventilation, cardiac arrest occurred and the patient died.
The physicians suggest that "...caution should be exercised when treating erectile dysfunction with sildenafil in patients receiving protease inhibitor-based HAART until more data are available."
Ref: Lancet 1999;35:2071-2072. Source: Reuters Health.
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Caution is warranted with the co-administration of these 2 drugs. However, given the number of doses of sildenafil used world-wide to date, many cases of co-administration with RTV must have occurred with no fatal adverse events previously reported. This man was in the first few weeks of RTV therapy which may have had an additional effect on the interaction.
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Castleman's Disease, a lymphatic hyperplasia, has two variants: hyaline vascular and the plasma cell type. In a letter to the editor, researchers from Ludwig Maximilians University in Munich report that they observed a clustering of rapidly progressing multicentric Castleman's disease of the plasma-cell type. All of the patients had HHV-8, while two had a history of Kaposi's sarcoma and a third had sarcomatoid Kaposi's sarcoma lesions. The authors assert that the clustering is unusual because it is a rare disease, it should be handled as a medical emergency, and symptoms of Castleman's disease occurred after starting highly active antiretroviral therapy (HAART). Investigators advise doctors treating HHV-8-positive patients with HAART to frequently monitor them for signs of Castleman's disease.
Ref: Zietz, Christian; Bogner, Johannes R.; Goebel, Frank-Detlef; et al. New England Journal of Medicine (17/06/99) Vol.340, No. 24, P. 1923. Source: CDC HIV/STD/TB Prevention News Update