Genetic Test Predicts Response to Maraviroc in Treatment-Experienced HIV Patients
Vancouver, British Columbia, Canada, July 22 2009 – A genetic approach to determining HIV tropism can be used to effectively identify patients who will respond to treatment with the CCR5 antagonist maraviroc, according to new data presented today at the 5th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention in Cape Town, South Africa.
Using screening samples from patients enrolled in the maraviroc treatment-experienced clinical trial program, results of this retrospective analysis showed that changes in HIV viral levels and the percentage of patients who achieved undetectable viral loads were comparable between those patients tested with HIV V3 Genotyping and Trofile™ (the recombinant-phenotypic assay originally used in the clinical trial program), indicating comparable accuracy of both tests at identifying treatment-experienced patients that will respond to treatment with maraviroc.
“HIV V3 Genotyping shows promise as a significantly faster and more cost-effective way to correctly identify patients who would benefit from CCR5 antagonists like maraviroc,” said Richard Harrigan Ph.D., lead investigator and Director of Research Laboratories, B.C. Centre for Excellence in HIV/AIDS, Vancouver, Canada. “Since the genotypic test is based on methods that are already widely used through the same labs that provide HIV drug resistance testing, this approach could become broadly available and conducted at the same time as resistance testing to determine susceptibility to all drugs, including maraviroc.”
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22 July 2009, Cape Town, South Africa –
The International AIDS Society (IAS) today announced the selection of Rome, Italy as host of the world’s largest open scientific conference on HIV/AIDS – the 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2011) – to be held from 17 - 20 July 2011 at the Auditorium Parco della Musica. The event will be organized by the IAS, in partnership with Istituto Superiore di Sanità (Italian National Institute of Health), which is the leading technical and scientific body of the Italian National Health Service.
High-risk genital wart strains increase HIV risk
Infection with one or more of the strains of human papilloma virus (HPV) associated with anal and cervical cancer increases the risk of contracting HIV.
Researchers from the Orange Farm circumcision study gathered information on the HPV infection status of 1683 men.
They found that the men infected with high-risk HPV strains were 4.5 times more likely than men without HPV to contract HIV.
Infection with low-risk HPV strains was not, however, associated with an increased risk of infection with HIV.
Once-daily Kaletra safe and effective in treatment-experienced patients
Previously treated patients can achieve good outcomes with once-daily lopinavir/ritonavir (Kaletra), and boost their adherence.
Kaletra is approved for once-daily dosing in combination with other antiretrovirals for individuals starting HIV treatment for the first time.
Researchers wanted to see how well this treatment strategy performed in patients with previous experience of antiretroviral therapy.
The study involved 600 people currently taking HIV treatment, but with a viral load above 1000 copies/ml. They were randomised into two equal groups, one taking the standard twice-daily dose of Kaletra (lopinavir/ritonavir 400/100mg), the other a once-daily dose (lopinavir/ritonavir 800/200mg).
After 48 weeks, equal proportions of patients in the two arms (52% vs 55%) had an undetectable viral load (below 50 copies/ml), the goal of antiretroviral therapy. Increases in CD4 cell count were also comparable between the two groups.
An advantage of once-daily dosing was better adherence.
New integrase inhibitor looks good in early clinical trials
Glaxo SmithKline’s experimental second-generation integrase inhibitor GSK-572 has performed well in early clinical trials.
In a phase 2a, ten-day, study, 35 HIV-infected, treatment-naive people were randomised to receive either monotherapy with the drug or a placebo.
Significant falls in viral load were observed in patients taking all doses of the drug. Within 2 weeks, a 2.46 log drop in viral load, from baseline, was seen in this monotherapy arm. As well, there appears to be a significantly long half-life. To this point, there appears to be no cross-resistance with raltegravir or elvitegravir.
Especially good results were achieved by individuals taking the 5mg dose, with 70% having a viral load below 50 copies/ml at the end of the study, and 90% a viral load below 400 copies/ml.
The most commonly reported side-effects were diarrhoea, tiredness and headache. With the exception of headache, these were more common in the placebo arm.
The 50mg dose will be studied in a 24-week phase IIb trial starting later this month, followed, hopefully, by a phase III trial.
5 abstracts, either oral or poster, were to be presented at this Conference.
Science has paid insufficient attention to gender identities
(masculinities and femininities) and as a result has failed to
consider the meanings and social context underlying risky
sexual practices. Dr. Jewkes is Director of the Medical
Research Council’s Gender and Health Research Unit in
Pretoria, South Africa. Dr. Jewkes’ ethnographic and epidemiological
research on gender and sexuality includes the
evaluation of Stepping Stones, an HIV prevention programme
that aims to improve sexual health by using participatory
learning approaches to improve knowledge, risk awareness
and communication skills. The research shows reductions in
new herpes simplex type 2 (HSV-2) infections and men’s use
of violence against women. According to Dr. Jewkes, the
consideration of sexual practices within a broader context of
gender identities may help explain why efforts to change
isolated sexual behaviours (such as promoting consistent
condom use) have met with resistance, and may also explain
the relatively greater success of interventions that have
sought to change gender norms.
Have HIV Programmes
Strengthened Health Systems?
Yes. At a two-day pre-conference meeting, one-hundred
health systems and HIV researchers examined existing
evidence on this crucial question and found that HIV
scale-up has enhanced and strengthened key components
of health systems:
1. Health expenditures have increased.
2. The overall health workforce has become more
innovative.
3. Human rights, social determinants and issues of
equity are now at the forefront of primary health care.
4. There is global solidarity around the need for
strengthened health systems.
5. Accountability and effectiveness of public health
programmes and services has improved.
While scale up of HIV treatment has enabled the building
of emergency systems to put large numbers of people on
antiretroviral therapy, HIV programmes must now evolve to
allow for management of HIV as a chronic health condition.
Building integrated health services for broader health
outcomes for people living with HIV is also crucial. Participants
agreed that health systems research can demonstrate
how to improve social health insurance, programme
effectiveness, and build up and retain the health workforce.
Track B
Daily summary
21 July (Tuesday)
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Under the title of “Old Doors Closing, New Doors Opening” important new data from clinical trials was presented today. We will particularly highlight the 96-week follow-up data from the MERIT study (as observed at Week 48, when patients were reclassified according to the enhanced tropism assay, maraviroc virologic response was non-inferior to the comparator arm) , the next generation once-daily integrase inhibitor from GSK (following a 10-day administration in ART-naïve subjects, there was a significant dose-response effect, with 70% of patients becoming undetectable with the highest dose of 50 mg) , and the MONET trial (treatment simplification from Truvada/Darunavir to Darunavir alone achieved equivalent virologic response to Truvada/Darunavir continuation), this strategy could be associated with significant cost savings. A more detailed summary of these important studies, some of which have the potential to change practice, can be found in the corresponding reports of the session.
Another session highlighted significant differences in the spectra of causative microbiologic organisms in bacterial infections between HIV-positive and HIV-negative populations in both high- and low-income countries. For instance, unlike HIV-negative patients, Streptococcus pneumoniae appears to be a significant cause of bloodstream infections in Spain and of pulmonary infections with high rate of drug resistance in Uganda.
There was a very good symposium on antiretroviral resistance that discussed recent data from the resistance meeting that took place in Florida in June. Another presentation did an update on resistance from the developing world and the different pathways of resistance that the different clades of the virus can take; an issue that can become relevant in the management of patients with HIV in the South. Finally Dr. Boup made a presentation about the peculiar patterns of resistance of HIV-2.
Community
Daily summary
21 July (Tuesday)
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Daily Summary
Tuesday July 21 2009
Dr Wafaa El-Sadr from the US expressed her major concern that countries of the North are starting to think that HIV is not an emergency anymore when only one third of the people who need treatments are getting it. HIV is a chronic disease that requires major adaptation to the health systems of countries to treat it effectively but here will be gains in treating other infectious diseases and other diseases generally if we provide enough resources to get HIV right. It is unacceptable to reject HIV-positive pregnant women who arrive at clinic needing care, or to reject HIV-positive children when it known that the chances of their dying without treatments will be around 50%.
The community engagement tour has been a highlight of the Conference for me so far. MSF plays a wonderful role in these health care settings despite huge obstacles. They provide integrated care for thousands of people living with HIV and TB who attend the daily clinics here. The challenges they face though are enormous with a scarcity of human resources caused by the difficulty to retain clinical staff on such low salaries: as someone explained to me some of the health care workers could receive higher wages working in an hotel in Cape Town than they can at their facilities. But many do the work because of the huge need and the knowledge that they are helping to keep people alive by delivering the best clinical care that is possible. It was confronting to see the numbers of children being cared for by their grandmothers and aunts as they have lost their parents to HIV.
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A mathematical model from the Harvard School of Public Health, based on the population of Washington, DC has found that recalling every adult for annual HIV screening and treating every HIV-positive person with antiretrovirals as soon as they were diagnosed would result in a 30% decline in the proportion of the HIV positive population who had non-suppressed viral loads (defined as over 500 copies/ml in this study), in the event of realistic takep of tests and treatment.
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Two studies using new methods to detect changes in arteries that could give rise to cardiovascular disease have generated differing results.
In one, a study using a sensitive ultrasound test found that long-term HIV infection was independently associated in men with an impairment of the artery’s ability to expand, with higher systolic blood pressure as the result. However, this impairment was only seen in men who had had HIV for more than 15 years.
In the other study, researchers found an apparent effect on heart function in patients who had only been on antiretroviral therapy for a month. They used a sophisticated series of PET and CT scans to map coronary perfusion – blood flow through the coronary arteries and into the heart muscle. They found there was a 31% reduction in coronary blood flow in patients taking HIV therapy when subjected to maximum cardiac stress.
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Track B
Session summary
WESY2, Challenges in Treatment and Care
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Powderly discussed the issue of when to start ART in patients with advanced disease and opportunistic infections. Citing the ACTG A5164 study and the SAPiT study of the optimal timing of ART in the treatment of TB, as well as an observational study of critically ill patients in Brazil that was presented in Mexico City, he noted that there is growing evidence of a benefit of ART as soon as is possible and logistically feasible to ensure adherence and access to an unbroken drug supply in people with advanced disease and acute opportunistic infections. He noted that more data will be forthcoming on the optimal timing of ART and TB initiation, and that there may be important differences between individual OIs that require further study; for example, a small uncontrolled study of ART in cryptococcal meningitis from Zimbabwe from CROI 2009 showed a higher mortality when ART was introduced earlier.
Dr. Gallant summarized approaches to second-line antiretroviral therapy by discussing when to switch therapy. Earlier switches are associated with better outcomes, as resistance develops in the face of even low level HIV replication. In resource rich settings the typical sequential treatment algorithm for patients with virologic failuare after starting on 2 NRTIs and an NNRTI is to switch to a second line regimen constructed around a boosted PI. Data suggests that a boosted PI alone may be potent enough for many patients. Continued use of 2 NRTIs is most commonly used, but there are options to use a new agent such as raltegravir, maraviroc, or etravirine. For patients initiated on a boosted PI combination, a single M184 mutation is the most likely resistance pattern that would be encountered with virologic failure. Second options for such patients include continued boosted PI therapy and other NRTIs with enhanced adherence recommendations, or a boosted PI with another active drug in the NNRTI, CCR5 inhibitor, or integrase inhibitor classes. In the developing world second line options differ. The response to the initial combination is similar in developed and developing countries. However, the use of CD4+ count or clinical monitoring to gauge when to switch therapy will likely result in a delay in treatment modification until a time when the virus has more resistance than what would typically be encountered in the developed world. Many patients failing first line therapy in the developing world have virus that is so resistant there may not be remaining NRTI options. The typical second approach is to use two other NRTIs, that have not been used previously, plus a boosted PI. An important change to ART treatment patterns in the developing world should include avoidance of thymidine analogs because of toxicities and the propensity to develop cross resistant virus after failure. The availability of viral load monitoring is essential to make wise decisions. Finally, in a general context there is a need to bridge the gap between patterns of therapy in the developed and developing world.
Track B
Session summary
WELBB1, Late Breaker B
Dr. Squires presented the 84 weeks results of a simplification trial to test the effectiveness of an unboosted PI regimen in patients with virologic suppression. Subjects (n=515) who entered the trial started on ABC/3TC + boosted ATV, were treated for 36 weeks, and were randomized to continue therapy (n=209) or drop the RTV and continue on ABC/3TC + ATV (n=210) if their viral load was <50 c/mL prior to week 36. The primary endpoint was the proportion of subjects with VL<50 c/mL at week 84 by TLOVR analysis. Subjects were predominantly White (63%) and men (84%), with a median viral load of 5.05 log and CD4+ count of 200. At week 84, 86% of subjects on ATV and 81% on ATV/r had viral loads <50 c/mL (-5%; 95% CI -1.75, 12.48, p=0.140). Similar results were seen in subjects with baseline viral loads < or >100.000 c/mL. CD4+ count changes were similar in both groups. There were a total of 8 virologic failures, 1 in the ATV group and 7 in ATV/r group, and treatment emergent mutations was seen in the one failure in the ATV group (M184) and no mutations in the ATV/r group. Treatment related adverse events included grade 2-4 hyperbilirubinemia (14% in the induction phase and 4% in the maintenance phase in the ATV arm versus 12% in the induction phase and10% in the maintenance phase in the ATV/r arm. Decreases in total and LDL cholesterol and triglycerides were observed following discontinuation of RTV in the unboosted ATV arm. In conclusion, unboosted ATV had comparable activity with less hyperbilirubinemia and a more favorable lipid profile than continued boosted ATV.
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Dr. Gandhi's study examined the potential of treatment intensification to reduce low level, detectable viremia in patients with quantifiable viral loads <50 c/mL to determine if this low level viremia represents replicating virus or virus release from latent reservoirs. Subjects received raltegravir or placebo for 12 weeks, and then crossed over to the alternative experimental arm and followed until week 24. The study included subjects with baseline VL >100,000 c/mL and had a screening VL>1 c/mL. 125 subjects screened 60% with detectable VL, 53 were enrolled, and 49 contributed data. The median viral load of subjects was 1.7 c/mL. There were no differences between the absolute or change in viral load between the two groups or following the switch to the alternative treatment. There was a trend towards a higher CD4+ count following the addition of raltegravir that reversed after its withdrawal. These data argue against the hypothesis that ongoing cycles of replication are the main source of residual plasma viremia.
Community
Session summary
TUSY3, New Strategies and Controversy in HIV Testing and Surveillance
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TUSY3 New strategies and controversy in HIV testing and Surveillance
Tuesday 21 July 14.30 – 1600
HIV testing and surveillance issues are becoming an increasingly critical aspect to many of the emerging debates about not only testing and treatments access, but also the appropriate focus of service delivery. Covering the increasing use of surveillance surveys – not just for collection of prevalence data, but also now including a number of other features such as CD4 levels, and incidence data, the question was repeatedly posed as to whether the cost and data burden of these large country wide survey programmes are really going to be measured as justifiable or cost effective.
The speakers agreed that current tools are not only imperfect, but as has been spoken about in other sessions at this meeting, it is also apparent that we often do not have the right tools to know if interventions being rolled out are working. As Maestro from the US observed, the most critical measure of a HIV epidemic – the incidence of HIV – is the target for many efforts from the WHO and others to develop new tools that can guide the next billions of dollars to be spent in the HIV response.
Lo from Germany also spoke to the data we do have which shows what large behavioural impact there is when people who receive counseling and testing know their status. She pointed to data that underlined this not only for those who are HIV positive, but also those in serodiscordant relationships.The power of community based interventions to increase testing, but that are linked to treatment and care services, and target also the decreasing of discrimination, were highlighted.
Finally, Amon from Human Rights Watch in New York gave a powerful overview of the the testing issues for those “hard to reach populations”. In his opening remarks it was framed that there was really no easy group, but that clearly marginalized populations were a focus – highlighting MSM, prisoners, and migrants. The criminalization of sexuality, the segregation and neglect of many in prison settings, and the discriminatory laws and policies in place around the world that deny rights to migrant populations were all described. Amon argued that unless human rights were set as the context for these problems then structural barriers for testing and treatments would continue. Government leadership and cross sectoral responses beyond only the health sector were emphasized as the only way forward.
Track B
Session summary
WEBS1, Hepatitis B and C
Pointing out that the availability of the HCV replicon has made it easier to identify HCV treatment target and assess responses, Bhagani first gave an overview of the substantial HCV drug pipeline which includes protease inhibitors (the closest to the market being telaprevir and boceprevir), polymerase inhibitors, entry inhibitors and others such as immune modulators. He however pointed out that many questions remain including how the findings apply to HIV-infected patients (as no study involved HBV/HIV co-infected patients), potential emergence of resistance and drug-drug interactions. He then drew attention to the new epidemic of acute HCV infection among MSMs which has spread beyond Europe. In concordance with what Lewin discussed earlier, he pointed that progression to end-stage liver disease has improved in the HAART era, but remains significantly higher in HIV/HCV than HCV-only patients. Also, better control glucose metabolism is associated with improvement in liver fibrosis in HIV-infected patients.
The speaker then went on to outline factors predictive of clinical response to HCV, including acute infection, low viremia, younger age, lack of stage ¾ fibrosis or steatosis, ethnicity, low BMI, high CD4 and lack of insulin resistance. Finally he discussed potential strategies to maximize treatment response. We’ll highlight that longer duration of undetectability on treatment increases chance for SVR, which is why the current guidelines total duration of HCV treatment depends on the speed of achieving undetectability. Increasing the interferon dose did not alter the response rate.
Finally, regarding HBV, he highlighted the importance of lamivudine resistance on disease progression, and the caution about the efficacy of entecavir on HIV replication.
Rapporteur report
Track B report by Ian Frank, Pablo Tebas, Renslow Sherer and Roger Bedimo
In a substudy of the GRACE trial of boosted darunavir in antiretroviral naïve women, changes in immunological markers following therapy were described in 19/32 virologically suppressed subjects. CD4 counts increased 195 cells/mm3 at week 48. Decreases in percent CD38+DR+CD4+ and %CD38+DR+CD8+, markers of immune activation towards, but not to control levels seen in an HIV uninfected control group were seen. Functional recovery, as assessed by capacity to proliferate and the expression of intracellular cytokines by CD4+ cells, was observed.
The TRIO study evaluated open label raltegravir, boosted darunavir, and etravirine in highly treatment experienced patients. 103 subjects were enrolled with a baseline viral load of 4.0 log10 c/mL, a median CD4+ count of 255, and 13 years of treatment experienced. The proportion of subjects with viral loads <50 copies/mL at weeks 24 and 48 were 90% and 86% respectively, demonstrating the durability of the response.
Trottier and colleagues analyzed the contribution of NRTIs to a salvage combination in highly treatment experienced patients who received raltegravir, maraviroc, etravirine, and NRTIs. There were no active NRTIs by genotype. There was an inverse correlation between number of NRTIs prescribed and probability of achieving a viral load <50 c/mL. [This information was presented similarly at CAHR 2009 – Vancouver]
IAS 2009: The Numbers
• 5,80+ participants
• 360 volunteers
• 1,000+ Facebook fans
• 123 countries represented
• 197 scholarship recipients
• 299 media representatives
• 2,400+ abstracts submitted,
with 1,550+ accepted
• 59 total sessions
• 12 plenary speeches
• 5 special sessions
• 49 exhibits
• 35 satellite meetings
• 6 scientific awards
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