2007
Download .pdf document of this issue.
EDITORIAL
- EDITORIAL
- The latest edition of the i-Base Introduction to Combination Therapy is included as a supplement to this issue of HTB. The November 2007 edition has been updated to include recent changes to the European and US guidelines. We have reduced the size, rewritten the section on choice of treatment, included several new graphs and tables, including a pull-out colour chart of ARVs, and added pages to record CD4, viral load, and other test results.
CONFERENCE REPORTS:
8th International Congress on Drug Therapy in HIV Infection,
12–16 November 2007, Glasgow
- 11th European AIDS conference (EACS)
- We include several reports from this recent European conference, held this year in Madrid.
- New European guidelines launched
- The conference saw the launch of three sets of very useful summary guidelines, produced by the European AIDS Clinical Society.
- Saquinavir/r non-inferior to Kaletra at week 48 (Gemini study)
- Simon Collins, HIV i-Base
- The Gemini Study was a 48-week prospective, open-label trial that randomised 337 treatment-naïve patients to either saquinavir/r or lopinavir/r, using tenofovir and FTC as background nukes.
- Darunavir once-daily is non-inferior to lopinavir/r in treatment-naïve patients at 48 weeks (Artemis study)
- Simon Collins, HIV i-Base
- In an oral late breaker presentation, Nathan Clumeck presented results from a randomised, multinational (26 country) study, comparing darunavir once-daily to lopinavir/r (once- or twice-daily) in almost 700 treatment-naïve patients. Use of lopinavir/r once-daily by some US patients was a patient/doctor choice and not subject to randomisation.
- Tesamorelin (TH9507) reduces abdominal fat in patients with HIV-related lipodystrophy: 52 week results
- Simon Collins, HIV i-Base
- In another late breaker at the meeting, Steve Grinspoon from Massachusetts Medical School, presented 52-week results from the use of the investigational growth hormone releasing factor (GHRF) tesamorelin (2mg/day) to reduce visceral adipose tissue (VAT). [1]
- Drug interaction studies presented at EACS
- The following summary of drug interaction studies was produced by HIV-druginteractions.org
- The effect of tenofovir/emtricitabine on the pharmacokinetics of nevirapine (200 mg twice daily) was studied in seven HIV-positive, African-American subjects.
TREATMENT ACCESS
ANTIRETROVIRALS
SIDE EFFECTS
- Case report of efavirenz-associated nephrolithiasis
- Simon Collins, HIV i-Base
- Hassane Izzendine and colleagues from Hôpital Pitié-Salpêtrière reported a case of efavirenz-associated nephrolithiasis in a letter to the September 2007 issue of AIDS. [1]
- Yellow card reporting scheme for doctors and patients in the UK
- The MHRA and the Commission on Human Medicines (CHM) run the UK’s spontaneous adverse drug reaction reporting scheme - called the Yellow Card Scheme. This receives reports of suspected adverse drug reactions (ADRs) from healthcare professionals. More recently the scheme was extended to included direct reporting by patients.
PREGNANCY AND MCTC
- US updates guidelines on use of ARVs during pregnancy
- The Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States have undergone a complete revision and reorganisation to reflect important new information, and to make them more user-friendly.
- Perinatal transmission of HIV in England 2002-2005
- Polly Clayden, HIV i-Base
- A report published by the NHS Audit, Information and Analysis Unit (AIAU) in collaboration with the National Study of HIV in Pregnancy and Childhood (NSHPC), and the Children’s HIV Association of the UK and Ireland (CHIVA), describes the circumstances in which infants are born HIV-positive, despite well documented interventions that can reduce mother to child transmission to almost zero in this country.
- Risk factors for in utero or intrapartum mother-to-child transmission in Thailand
- The risk factors for mother-to-child transmission (MTCT) of HIV have been well documented: high maternal viral load, low CD4, sexually transmitted infections during pregnancy, prolonged ruptured membranes and vaginal delivery.
DRUG INTERACTIONS
- New drug interaction summary tables
- HIV-druginteractions.org has compiled three new summary tables relating to interactions with the latest and most developed pipeline drugs and a similar chart for oral contraceptives.
- Recent reviews from HIV-druginteractions.org
- The findings of this study add weight to an underlying concern of an association between tenofovir-induced nephrotoxicity and concomitant boosted protease inhibitor treatment.
VACCINE RESEARCH
- Merck HIV vaccine trial is unblinded
- Round up of news posted to Treatment Action Group (TAG) basic science blog.
- It was announced on 13 November that the STEP trial will be unblinded; all 3,000 participants will be told whether they received vaccine or placebo and informed of their anti-adenovirus antibody titer.
OTHER NEWS
- IAS statement on US policy for HIV-positive visitors
- The International AIDS Society (IAS) would like to express concern over the proposed United States Department of Homeland Security (DHS) ruling, docket number USCBP-2007-0084, “Issuance of Visa and Authorisation for Temporary Admission into the United States for Certain Nonimmigrant Aliens Infected with HIV.” Public comment on this proposed ruling is due on December 6, 2007, and we attach our comments with this statement.
EDITORIAL
- EDITORIAL
- This issue leads with a report presented to the BHIVA conference from the latest BHIVA audit on treatment of naive patients in the UK. Some of the findings make uncomfortable reading.
CONFERENCE REPORTS
TREATMENT ACCESS
ANTIRETROVIRALS
- Atripla approved in Europe as switch option for suppressed patients
- On 18 October 2007, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) issued a positive opinion on the Marketing Authorisation Application for the fixed-dose triple combination Atripla (efavirenz600mg/FTC200mg/tenofovir300mg).
- Maraviroc approved in Europe for treatment-experienced CCR5-tropic patients
- On 24 September 2007, maraviroc (trade name in Europe Celsentri) was approved in Europe for treatment-experienced patients who have CCR5-tropic HIV infection. Maraviroc is a CCR5 inhibitor manufactured by Pfizer with the trade name Celsentri in Europe and Selzentry in the US.
- Paediatric formulation of fosamprenavir approved in Europe
- On 13 September, the EMEA issued a decision to extend the indication for fosamprenavir (Telzir) in combination with ritonavir to include adolescents and children of six years and older.
- Raltegravir approved in the US
- On 12 October 2007, the Food and Drug Administration (FDA) granted accelerated approval for raltegravir (trade name Isentress), the first integrase inhibitors. Approval is based on efficacy and safety data from two double-blind, placebo-controlled studies (BENCHMRK 1 and 2) in 699 treatment-experienced HIV-1 infected adult patients (with documented resistance to at least 1 drug in each of NRTIs, NNRTI and PI classes), randomised 2:1 to receive either active drug or placebo, plus optimised background treatment.
- EMEA recommends reinstating license for Roche’s nelfinavir
- On 20 September 2007, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended the lifting of the suspension of the marketing authorisation for nelfinavir (Viracept, manufacutred by Roche) and the re-introduction of the medicine onto the market in the European Union.
- Roche withdraw application for Biojector 'needle-free' option for T-20
- On 3 October, Roche and Trimeris announced that they are withdrawing a supplement application for approval to market Biojector B2000 as a 'needle-free' option for delivery of T-20 (enfuvirtide). [1]
WOMEN'S HEALTH
PREGNANCY AND MTCT
PAEDIATRIC CARE
HEPATITIS COINFECTION
ARV4IDUs
VACCINE RESEARCH
- Merck HIV vaccine trial halted by DSMB for lack of efficacy
- Richard Jeffreys, TAG
- Extremely grim news for the HIV vaccine field: The phase IIb efficacy trial of Merck’s adenovirus-based HIV vaccine candidate (MRKAd5, also recently referred to as V520) has been stopped after an interim analysis by the trial’s Data Safety Monitoring Board (DSMB) found no differences between the placebo and vaccine groups for either of the trial’s primary endpoints: acquisition of HIV infection or post-infection viral load levels (in this case, the geometric means of two viral load measurements taken 8 and 12 weeks after infection).
EDITORIAL
- EDITORIAL
- This issue includes the first coverage from the 4th IAS Conference and 9th Lipodystrophy Workshop, both held in Sydney in July.
TREATMENT ALERT
- Update on nelfinavir recall: plan for safety registries
- Simon Collins, HIV i-Base
- We included several pages in the last issue of HTB covering the recall, due to contamination, of the protease inhibitor nelfinavir,
manufactured by Roche Laboratories. This recall later resulted in suspension of Roche’s license to distribute the drug.
CONFERENCE REPORTS
- 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention 22-25 July 2007, Sydney
- Over 5,000 delegates from 133 countries registered for the meeting this year. For attendees from Europe, Africa and the
US, the distance and cost probably limited attendance to the meeting. For those lucky enough to be able to attend, the
meeting included a wealth of new data in many aspects of HIV research. Over 3,100 original abstracts were submitted and
978 abstracts were accepted for oral or poster presentation.
TREATMENT STRATEGIES
- HIV viraemia may explain increased risk of cardiovascular disease, death and other
serious events in patients interrupting treatment in the SMART trial: new study to
randomise patients with CD4 counts >500 to start immediate treatment or defer to <350
cells/mm3
- Simon Collins, HIV i-Base
- The START trial is a critical study that has the potential to change not only clinical management and challenge many current assumptions about risks and benefits or treatment as significantly as the SMART study last year.
- CD4 increases in immunological non-responders despite suppressive therapy following
switch to nuke-sparing regimen of ATZ/SQV/r
- Simon Collins, HIV i-Base
- In the symposium on HIV pathogenesis on the first day of the conference, Michael Lederman referenced a study showing that up to 20% patients fail to achieve CD4 increase to greater than 350 cells/mm3 after five years of suppressive therapy (below 95th percentile of HIV-negative population).
- Darunavir/r shows superiority over lopinavir/r at 48 weeks in TITAN trial
- Simon Collins, HIV i-Base
- The results by baseline sensitivity indicate that while lopinavir/r will not rescue patients with loss of sensitivity to darunavir/r, darunavir is certainly more active than lopinavir in patients with loss of sensitivity to lopinavir.
- Maraviroc fails to show ‘non-inferiority’ to efavirenz in
treatment-naïve patients: 48 week results
- Simon Collins, HIV i-Base
- Failure to achieve non-inferiority at suppression to <50 copies/mL in the study was dependent on the choice of –10% as a lower cut-off, although other FDA regulatory studies have set this at 12%. However, this still leave the scenario of having a drug that is 9% less potent than standard of care.
- Importance of using maraviroc in combination with other
active drugs in treatment-experienced patients
- Simon Collins, HIV i-Base
- The underperformance in important patient subgroups (low CD4, high viral load, and fewer active drugs in the regimen) clearly supported the choice to develop maraviroc as a twice-daily drug.
- Week 48 raltegravir results in treatment-naïve Phase II dose-finding study
- Simon Collins, HIV i-Base
- As this issue of HTB went to press (5 September), the US FDA advisory committee recommended approval of raltegravir for treatmentexperienced
patients who have ongoing viral replication despite existing treatment.
- DUET studies clarify antiviral efficacy of etravirine and
cross-resistance profile to other NNRTIs
- Simon Collins, HIV i-Base
- The DUET studies are the first trials to demonstrate a clear antiviral benefit of etravirine in treatment-experienced patients.
- Boosting atazanavir in treatment-naïve patients, and impact
on lipids after switching from lopinavir/r
- Simon Collins, HIV i-Base
- Although atazanavir/r is widely used in treatment-naïve patients, and widely used as a choice of switch drug in patients experiencing tolerability problems with efavirenz or lopinavir/r, there is limited data in naïve patients (and for whom it still not indicated in Europe).
- Saquinavir/r vs lopinavir/r in treatment-naïve patients
- Simon Collins, HIV i-Base
- Francois Raffi from University Hospital, Nantes, France, presented interim results (24 week) from the Gemini study, which randomised 337 treatment-naïve patients to twice daily regimen of SQV/r (1000mg/100mg BID) or standard dose lopinavir/r BID.
- Fosamprenavir/r vs atazanvir/r in treatment-naïve patients
- Simon Collins, HIV i-Base
- Whatever the power of the study, (p-values for the statistical virological difference between the two arms was p=0.3), these results do not appear to show any benefit of using fosamprenavir over atazanavir.
- Antiretroviral therapy initiated before 12 weeks of age reduces early mortality in young infants; interim results from the CHER study
- Polly Clayden, HIV i-Base
- Running 100 PCR viral load tests in order to diagnose 7-8 HIV-positive babies early enough to benefit from immediate treatment is just not going to be feasible in many places (eg Malawi). The ratio drops further if AZT and NVP are used together, as currently happens in the Western Cape, South Africa.
PREGNANCY, BREASTFEEDING & MTCT
HEPATITIS COINFECTION
CONFERENCE REPORTS
- 9th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV
19-21 July 19-21 2007, Sydney
- Michael Dube, for NATAP.org
- Overall there continues to be a progressive evolution of our understanding of the causes of lipodystrophy, dyslipidemia, cardiovascular disease, and other adverse effects of ART. While certainly there have been no major breakthroughs in management, the availability of agents with lesser effects on these parameters and a few therapeutic interventions have begun to be applied.
- Can nevirapine be safely substituted for other agents in those with high CD4 cell counts and virologic suppression?
- Michael Dube, for NATAP.org
- It should be added that these patients had undetectable viral load at the time of the switch. No information was provided about the choice of dosing, and whether patients switched to the full nevirapine dose or whether they use the 200mg once-daily dose for the first two weeks. There is still no clear evidence to inform this decision.
- Do children with perinatally acquired HIV infection have
problems with metabolism and body shape?
- Michael Dube, for NATAP.org
- Total fat and limb fat were lower in both PI and no-PI groups but even though BMI was less in the HIV-infected subjects in general, trunk fat was not different in the PI-treated individuals - suggesting that perhaps PIs led to greater trunk fat accumulation in these patients.
- The growth hormone releasing factor analogue tesamorelin (TH9507) reduces visceral fat, but what else does it do?
- Michael Dube, for NATAP.org
- GHRF is made by the hypothalamus gland and stimulates the pituitary gland to produce growth hormone. But growth hormone therapy is associated with many side effects, including diabetes/impaired glucose tolerance/insulin resistance as well as various aches and pains like carpal tunnel syndrome and joint aches.
- Does diabetes have the same impact on cardiovascular risk in HIV-infected patients as it does in the general population?
- Michael Dube, for NATAP.org
- The multicentre, multi-continent DAD study has contributed greatly to our increased understanding of risk factors for development of cardiovascular disease in HIV-infected individuals. Signe Worm from Copenhagen presented an analysis of just how much does a diagnosis of diabetes contribute to the risk of myocardial infarction.
- Can nucleoside RT inhibitors directly cause insulin resistance?
- Michael Dube, for NATAP.org
- Current dogma has early insulin resistance from ART blamed on protease inhibitors, and late insulin resistance attributed to lipoatrophy induced by nucleoside drugs. But studies in healthy subjects have suggested that at least some NRTIs may cause early insulin resistance as well.
- Do dyslipidemia, insulin resistance, and body shape changes differ according to race/ethnicity?
- Michael Dube, for NATAP.org
- Data presented by Carl Grunfeld of UCSF from the CPCRA FIRST study extend existing data on the effects of race/ethnicity on metabolic and body composition variables in subjects initiating ART. This was a large (400 subjects) multi-ethnic (61% African-American, 28% white, 11% Latino) cohort that is noteworthy because it examined changes over time in these parameters.
- Is lipoatrophy associated with vascular dysfunction?
- Michael Dube, for NATAP.org
- Lipoatrophy is associated with a variety of adverse cardiovascular risk factors such as dyslipidemia and insulin resistance, but as yet there has been no good evidence that cardiovascular event rates are higher or vascular dysfunction is greater among those with lipoatrophy or lipohypertrophy.
TREATMENT ACCESS
The following round-up of articles and links relates to treatment access news over the last month.
- Mbeki draws international scorn for firing deputy health minister
- Treatment Action Campaign
- South Africa's Presdent Mbeki has drawn widespread criticism for his recent sacking of his Deputy Health Minister. South Africa has the highest number of HIV-positive people (>5 million) including 19% of adult population, and a scandalous history of denial of both HIV and the benefits of HIV treatment.
- FDA approval of generic ARVs
- Since the last issue of HTB, the US Food and Drug Administration (FDA) has granted tentative approval for the following new generic ARV products.
- Lesotho to revise national guidelines to include tenofovir first line
- The revised guidelines are still in draft form but have been provisionally approved by the Director General of Health at the Ministry of Health and Social Welfare (MOHSW) and are awaiting final approval.
PREGNANCY AND MTCT
- UK (BHIVA) pregnancy guidelines online for comment
- Polly Clayden, HIV i-Base
- The 2007 Pregnancy Guidelines are posted for consultation on the BHIVA site. Following the consultation and any revisions,
the BHIVA council will ratify the final version and they will be presented at the BHIVA Autumn conference.
- Increased rates of pre-term delivery are associated with the Initiation of HAART during pregnancy: a single-centre cohort study
- Polly Clayden, HIV i-Base
- Where this study differs from previous reports, is the finding that initiating HAART during pregnancy, regardless of indication, was associated with more PTD than if HAART was started before pregnancy. If these observations are confirmed, the dilemma will be the timing of initiating therapy for
mothers taking a short course of HAART for prevention of HIV mother-to-child transmission only. Early to ensure undetectable viraemia by the time of (pre-term) delivery or later to avoid initiating severe (<32 weeks) pre-term delivery?
PAEDIATRIC CARE
Download .pdf document of this issue.
- Editorial
- This issue leads with a treatment alert relating to the European recall of nelfinavir. As we went to press, the EMEA are working with Roche to formulate a patient registry to follow patients exposed to any level of contaminated drug. Further details will be announced as soon as they are available.
TREATMENT ALERT
- Roche recalls nelfinavir (Viracept) due to chemical impurity
- On 6th June 2007, Roche, in agreement and cooperation with Health Authorities (EMEA, Swissmedic and MHRA), recalled in Europe and some other world regions all batches of nelfinavir (Viracept) powder and tablets.[1] The US, Canada and Japan were not affected by this recall, as nelfinavir is manufactured by Pfizer in those countries.
- European Medicines Agency agrees on action plan following the recall of Viracept and recommends suspension of the Marketing Authorisation
- The European Medicines Agency today agreed on an action plan to follow-up patients who were exposed to contaminated Viracept (nelfinavir). Viracept, from Roche Registration Limited, is an antiretroviral medicine used to treat HIV-1 infected adults, adolescents and children of 3 years of age and older. It was recalled from the European market in early June 2007 because during the manufacturing process some batches had become contaminated with ethyl mesilate, a known genotoxic substance (harmful to DNA).
- EMEA questions and answers on the nelfinavir recall[1]
- The European Medicines Agency (EMEA) and the European Commission have now taken further steps following the recall of Viracept by Roche Registration Limited, because of a contamination with a harmful substance. Patients who may have been exposed will be closely monitored while more information
on the harmful potential of the contaminant is gathered. The EMEA has recommended to the European Commission that Viracept’s marketing authorisation be suspended.
CONFERENCE REPORTS
- Integrase inhibitors and resistance
- Simon Collins, HIV i-Base
- The workshop provided the first forum with numerous early studies addressing the issue of resistance to integrase inhibitors (INIs): Which key mutations develop and impact on drug sensitivity? How quickly do they develop? What is the role of polymorphisms in naïve and treated patients? What is the impact of cross class resistance? The relationship between integrase mutations and those in RT and protease genome; and the activity in HIV-1 subtypes and HIV-2.
- Treatment failure and tropism changes in maraviroc trial related to previously undetected CXCR4, rather than a mutational shift from CCR5
- Simon Collins, HIV i-Base
- Understanding the mechanism behind treatment failure with CCR5 inhibitors is as important as the new data provided on integrase: maraviroc is also already available in an expanded access programme and both maraviroc and vicriviroc are in Phase III studies.
- Mechanisms of failure to CCR5 inhibitors is not explained by mutation in the V3 loop, cross-resistance between CCR5 inhibitors is likely
- Simon Collins, HIV i-Base
- In vivo resistance to CCR5 inhibitors is not clearly understood. It does not seem to follow loss of sensitivity predicted by in vitro changes in the V3 loop and is limited by the small number of patient with clinical failure. Studies at the conference provided data on both maraviroc and vicriviroc.
- Higher risk of resistance using lopinavir/r monotherapy
- Simon Collins, HIV i-Base
- In the last presentation at the workshop, Constance Delaugerre presented an analysis of resistance results from the MONARK trial (Kaltera monotherapy).
- Macaque study shows similar protection from rectal exposure using 2-hour pre- and 24-hour post exposure prophylaxis with tenofovir plus FTC compared to daily regimen
- Simon Collins, HIV i-Base
- Results in macaque studies showing protection from HIV infection using daily tenofovir, and similar protection with reduced risk of resistance from using tenofovir plus FTC, provided sufficient confidence for large scale studies in humans to proceed, even though most of these studies have run into practical difficulties.
- Thirteen NNRTI mutations linked to resistance to etravirine (TMC-125)
- Mark Mascolini, for natap.org
- Tibotec researchers identified 13 non-nucleoside (NNRTI)-related mutations that blunted response to etravirine (TMC125) in the phase 3 DUET trials [1]. The most harmful mutations were among the rarest; and the worst responses to etravirine occurred in people with three or more of these mutations before beginning the new NNRTI. Several resistance experts at the workshop questioned the method Tibotec used to gauge the impact of various mutations on response to etravirine.
CONFERENCE REPORTS
- 14th Conference on Retroviruses and Opportunistic Infections
- 25-28 February 2007, Los Angeles
- Our final reports from this meeting include:
- Protease inhibitors in pregnancy
- Poly Clayden, HIV i-Base
- Since the report of hepatoxicity risk in women with CD4 counts above 250 cells/mm3 receiving nevirapine, the need has increased for more information on use of protease inhibitors in pregnancy.
- IDU-related studies at CROI
- Poly Clayden, HIV i-Base
- These reports will be included in a new electronic publication produced by i-Base called ARVs4IDUs. This will be a quarterly summary of research relating to injecting drug users and HIV, with the first issue available for the IAS conference in Sydney in July.
CONFERENCE REPORTS
- 8th International Workshop on Clinical Pharmacology of HIV Therapy
- Jennifer J. Kiser, Courtney V. Fletcher, for NATAP.org
- The 8th International Workshop on Clinical Pharmacology of HIV Therapy was held April 16-18, 2007 in Budapest, Hungary. 193 HIV clinical pharmacologists attended this year’s Workshop and more than half were new attendees. This year’s meeting included 80 posters, 30 platform presentations, six invited lectures, and a roundtable discussion on the optimal design of drug interaction studies.
- Introduction
- The 8th International Workshop on Clinical Pharmacology of HIV Therapy was held April 16-18, 2007 in Budapest, Hungary. 193 HIV clinical pharmacologists attended this year’s Workshop and more than half were new attendees. This year’s meeting included 80 posters, 30 platform presentations, six invited lectures, and a roundtable discussion on the optimal design of drug interaction studies.
- Drug-drug interactions
- Jennifer J. Kiser, Courtney V. Fletcher, for NATAP.org
- Previous studies have shown significant hepatotoxicity in healthy volunteers receiving rifampin in combination with saquinavir/ritonavir [1] and lopinavir/ritonavir [2]. At this year’s Workshop, a study detailing adverse events in healthy volunteers receiving the combination of rifampin and lopinavir/ritonavir was presented. [3]
- Pharmacokinetic data with existing antiretrovirals
- Jennifer J. Kiser, Courtney V. Fletcher, for NATAP.org
- Marta Boffito presented data on the plasma and intracellular concentrations of abacavir when given as either 600 mg once daily or 300 mg twice daily. [9]
- Antiretroviral pharmacokinetics in special patient populations
- Jennifer J. Kiser, Courtney V. Fletcher, for NATAP.org
- There are limited data on the appropriate dosing of antiretroviral drugs in patients with varying degrees of hepatic impairment.
- Pharmacology of investigational drugs
- Jennifer J. Kiser, Courtney V. Fletcher, for NATAP.org
- Maraviroc is a CYP3A4 and P-glycoprotein substrate, thus previous interaction studies have shown that a lower dose of maraviroc, 150 mg twice daily, should be used in combination with protease inhibitors (excluding tipranavir/ritonavir).
TREATMENT ACCESS
- G8 pledges to Africa are insufficient
- Some HIV/AIDS advocates and other groups have criticized the recent pledges from the G8 industrialised nations to Africa as “insufficient” and “part of a pattern of unfulfilled promises”.
- FDA approval of generic ARVs
- Since the last issue of HTB, the US Food and Drug Administration (FDA) has granted approval for Zidovudine (AZT) 100mg caps Cipla Laboratories, India (23 May 2007).
- Abbott sues ACT-UP Paris
- Abbott laboratories, manufacturer of lopinvir/r (Kaletra) and ritonavir (Norvir) has filed a lawsuit against ACT-UP Paris for organising a web protest which encouraged other advocates to use software to repeatedly access the Abbott site.
- UK’s DFID support of Thailand
- In a letter to Sarah Walden of People and Planet, Gareth Thomas from the UKs Department for International Development (DfID) supported the decision by Thailand to issue a compulsory license for HIV medications.
- Roche’s patent for hepatitis C drug challenged in India
- The Indian Patent Office has received a challenge against Hoffmann-La Roche’s patent rights for the hepatitis C drug Pegasys.
SIDE EFFECTS
PREGNANCY and MTCT
- Antiretroviral therapy and premature delivery in the United Kingdom and Ireland
- Polly Clayden, HIV i-Base
- Prematurity has been associated with use of antiretroviral therapy in pregnancy in some studies, but not in others.
- Early response to NNRTI-based antiretroviral therapy among women with prior exposure to single-dose nevirapine
- Polly Clayden, HIV i-Base
- A Zambian study authored by Benjamin Chi and co-workers, published in the 11 May 2007 edition of AIDS, evaluated outcomes for women receiving NNRTI-containing HAART after prior exposure to single dose nevirapine (NVP) from April 2004 to 31 July 2006. This was an open cohort evaluation in programme sites across Zambia.
- Mother to child transmission during exclusive breastfeeding
- Polly Clayden, HIV i-Base
- Breastfeeding remains an important route of mother to child transmission.
- Surveillance of mother-to-child-transmission programmes: the case for universal screening
- Polly Clayden, HIV i-Base
- A paper in June AIDS authored by Nigel Rollins and coworkers shows data first presented at World AIDS Conference in Toronto describing mother-to-child transmission in Kwazulu Natal, South Africa. [1, 2]
- Rapid progression in infants infected with HIV despite single dose nevirapine prophylaxis
- Polly Clayden, HIV i-Base
- A paper in AIDS authored by Wendy Mphatswe and coworkers reported findings from a study conducted in KwaZulu Natal, South Africa, to evaluate MTCT in a cohort of mothers and infants receiving single-dose NVP and disease progression in a subset of infants that were HIV-positive despite the NVP prophylaxis.
HEPATITIS COINFECTION
OTHER NEWS
ON THE WEB
Download .pdf document of this issue.
EDITORIAL
This issue of HTB continues our coverage from the 14th Conference on Retroviruses and Opportunistic Infections with reports on breastfeeding, MTCT, paediatrics and genetics.
CONFERENCE REPORTS: 14th Conference on Retroviruses and Opportunistic Infections, 25-28 February 2007, Los Angeles
- Introduction
- As usual with CROI, we include reports from this conference over several issues of HTB. The last issue of HTB included reports on new drugs, pregnancy, side effects, resistance, hepatitis, oncology, pharmacokinetics and drug interactions.
CONFERENCE REPORTS: 5th European HIV Drug Resistance Workshop, Cascais, Portugal, 29 March 2007
- Introduction
- The following reports from the 5th European Drug Resistance Workshop
TREATMENT ACCESS
PAEDIATRICS
- Increasing antiretroviral access for children
- Polly Clayden, HIV i-Base
- A paper from the American Academy of Pediatrics, published in the April 2007 edition of Pediatrics, describes the barriers to scaling up antiretroviral treatment for HIV-positive children and potential ways to overcome them; multiple paediatric organisations from across the world have endorsed this statement.
ON THE WEB
Download .pdf document of this issue.
- EDITORIAL
- One of the weaknesses of currently approved antiretroviral options is that even in treatment naïve patients, 20-30% of participants in clinical trials commonly fail to achieve viral suppression to below 50 copies/mL, limiting their long-term benefit from treatment.
INTRODUCTION
- Introduction
- The Annual CROI remains the most important HIV-focused medical conference, with many companies and researchers holding back data to present at this meeting. This year the meeting was held in downtown Los Angeles.
CROI: ANTIRETROVIRALS
- Raltegravir (MK-0518) Phase 3 trials show successful viral suppression in multi-drug resistant patients
- Simon Collins, HIV i-Base
- Probably the most important results at the 2007 conference were the late breaker abstracts from the newly-named integrase inhibitor raltegravir (formerly MK-0518). [1, 2]
- Maraviroc Phase2b/3 results in treatment experienced CCR5-tropic patients
- Simon Collins, HIV i-Base
- Results from a planned 24-week analysis of the Phase2b/3 studies of maraviroc (MVC) (Motivate 1 and 2) were presented by Howard Meyer and Elna van der Ryst in two linked late-breaker oral presentations. [1, 2]
- Phase 2 study of Gilead’s integrase inhibitor elvitegravir (GS-9137)
- Simon Collins, HIV i-Base
- Andrew Zolopa from Stanford University presented results from a Phase 2 study of Gilead’s integrase inhibitor elvitegravir (GS-9137) in treatment experienced patients.
- Phase 2 study comparing rilpivirine (TMC-278) to efavirenz in treatment-naïve patients: 48-week results
- Simon Collins, HIV i-Base
- 48-week results from the primary endpoint of the Phase2 TMC-278 C204 dose-finding study, of a second generation diarylpyrimidine NNRTI in development from Tibotec were presented in an oral session by Anton Pozniak form Chelsea and Westminster Hospital, London. Rilpivirine (TMC-278) is a once-daily compound that has a similar resistance profile to TMC-125 which is being researched as a second-line treatment after first NNRTI failure.
- PK results from heat-stable formulation of ritonavir
- Simon Collins, HIV i-Base
- Pharmocokinetic data for three prototypes of a heat-stable, meltrex formulation of ritonavir, was presented by George Hanna from Abbott Laboratories. When the development of meltrex formulation lopinavir/r was underway, many clinicians and advocates were equally keen to see the same approach applied to ritonavir.
- Use of low-dose rapamycin, a CCR5 suppressant, to increase potency of T-20 in vitro
- Simon Collins, HIV i-Base
- While difficulties of administration and side effects have generally restricted the use of T-20 to a relatively small number of patients, an independent investigator produced poster suggested a mechanism for increasing potency.
CROI: SIDE EFFECTS
CROI: PREGNANCY
- Pregnancy outcomes in the DART trial
- Polly Clayden, HIV i-Base
- The DART trial is a 6 year randomised trial of ART monitoring strategies in adults with symptomatic HIV and CD4 <200 cells/mm3 initiating ART in Kampala and Entebbe (Uganda) and Harare (Zimbabwe). Of the 3316 DART participants, 1867 are women of child-bearing age <45 years.
- 12 month response to HAART in women following exposure to prevention of mother to child transmission regimens
- Polly Clayden, HIV i-Base
- In an oral late breaker Francois Dabis presented findings from an evaluation of treatment response in women exposed to single dose nevirapine (sdNVP) and short course AZT alone or plus 3TC, for prevention of mother-to-child transmission (PMTCT) in Côte d’Ivoire between 2003 and 2006. [1]
CROI: RESISTANCE
CROI: HEPATITIS COINFECTION
- Sexual transmission of HCV in Brighton reported in HIV-positive and HIV-negative MSM
- Simon Collins, HIV i-Base
- Daniel Richardson presented updated results from the HCV screening programme run in Brighton. Although HCV screening is recommended in HIV-positive men on HIV diagnosis and prior to starting HIV treatment, UK guidelines do not routinely recommended HCV screening for HIV-negative men. Because Brighton has a high prevalence of HIV in MSM (approximately 13%, 30% of which are undiagnosed), and had reported sexual transmission of HCV in HIV-positive men, in 2000 they expanded their HCV screening programme to include all MSM.
- Hepatitis B drug entecavir reported to have anti-HIV viral activity in three patients
- Simon Collins, HIV i-Base
- Immediately prior to the conference, both the FDA and Bristol-Myers Squibb, the manufacturers of entecavir, issued a press release cautioning that this HBV drug may have anti-HIV activity. The data still remain controversial, as this was not reported in any earlier studies. The clinical importance of this finding, is the impact of entecavir monotherapy on the development of HIV drug resistance (the M184V mutation, shared with 3TC, FTC and abacavir), in the limited number of coinfected patients who are treated for HBV but not HIV.
CROI: MALIGNANCIES AND ONCOLOGY
CROI: EPIDEMIOLOGY
- Clade-B HIV-1 infection in Haiti predates global subtype-B virus
- Simon Collins, HIV i-Base
- Many questions over the epidemiology of HIV, including estimating cross-species infection into humans in the 1930s, and the worldwide development of different clades and sub-populations, have been convincingly explained over the last few years by a combination of phylogentic analyses and molecular modeling. Phylogentic analysis can track viral development and evolution over time by locating specific mutational changes that infer common ancestry. Molecular modeling uses the viral mutation rate to estimate a time frame back in time within which the changes would have occurred.
CROI: PK AND DRUG INTERACTIONS
- Drug interactions and pharmacokinetic studies
- Professor David Back, Liverpool University
- In this excellent review lecture, Dr Kashuba described the use of ‘cocktail’ studies (i.e., the simultaneous administration of more than one probe compound) to determine the activity of multiple enzymes and transporters. This procedure is now being used in drug development but there is ongoing debate as to the utility of the approach. Dr Kashuba reviewed current probes and cocktails and the potential value for understanding and predicting antiretroviral drug interactions.
ANTIRETROVIRALS
- Darunavir (TMC-114) approved in Europe
- Approval is for use in ‘highly pre treated adult patients who failed more than one regimen containing a protease inhibitor’ and was was based on safety and efficacy data from the POWER 1, 2 and 3 studies. A conditional marketing authorisation was granted to darunavir , taken in combination with ritonavir and other antiretrovirals, because of its benefits for HIV-1 infected patients, however, more evidence is yet to be provided. Additional safety and efficacy data will need to be submitted to the European Agency for the Evaluation of Medicinal Products (EMEA) annually until full authorisation is granted.
- No significant interaction reported between etravirine (TMC125) and raltegravir (MK-0518)
- Tibotec have contacted doctors in the UK to notify them of results from a drug interaction study in HIV-negative volunteers that supports use of both etravirine (TMC-125) and raltegravir (MK-0518) in the same combination.
- Future of second-generation fusion inhibitors less certain as Trimeris and Roche separate
- On 15 March 2007, Trimeris issued a press release announcing that a new agreement with Roche will “return of all rights to joint patents and other intellectual property related to next-generation HIV fusion inhibitor peptides to Trimeris. In return, Trimeris has agreed to pay Roche a nominal royalty on future net sales of TRI-1144 up to a specified limit.”
TREATMENT ACCESS
- Abbott situation worsens in Thailand
- In the last issue of HTB we reported the ongoing issue of access to drugs produced by the US manufacturer Abbott Laboratories for patients in Thailand. [1]
- FDA approval of generic ARVs
- Since the last issue of HTB, the US Food and Drug Administration (FDA) has granted tentative approval for the following new generic ARV products:
GUIDELINES
- BHIVA launch Standards for HIV Clinical Care
- The Standards for HIV Clinical Care, a new report by the British HIV Association, Royal College of Physicians, British Association for Sexual Health and HIV and British Infection Society. Standards for HIV Clinical Care was developed through a wide consultation process and was launched at the Royal College of Physicians on 20 March 2007. Key recommendations address:
ON THE WEB
- Guidelines and reports:
- A briefing paper highlighting the limitations of phylogenetic evidence in criminal trials of HIV transmission has been produced by the National AIDS Trust and NAM.
- EDITORIAL
- Welcome to our first double-issue of 2007. We lead with Gareth Hardy’s detailed review of recent research on the impact of HIV on gut mucosa - an area of that has become increasingly important in understanding the immunological effects from HIV infection.
SPECIAL REPORT
ANTIRETROVIRALS
- Pharmacokinetic study of Triomune-40 in Malawi: higher d4T exposure suggests importance of using lower dose formulations of d4T
- Simon Collins, HIV i-Base
- A study from Hosseinipour and colleagues published in the 2 January edition of AIDS reported results from a study in Malawi that could have clinical implications for use of Triomune, the most widely prescribed ARV regimen in resource-limited settings. Triomune is a fixed dose combination of d4T (stavudine), 3TC (lamivudine) and nevirapine.
- GSK stops development of brecanavir
- On 18 December, GlaxoSmithKline (GSK) announced that, due to insurmountable issues regarding formulation, the clinical development programme for the investigational HIV protease inhibitor brecanavir has been discontinued. Brecanavir had reached Phase II development.
- FDA analysis of predicted responses to tipranavir/r
- Simon Collins, HIV i-Base
- An analysis by the FDA, the US regulatory agency, of the clinical impact of resistance on the response of protease-inhibitor resistant patients to tipranavir/r (TPV/r) was published in the 11 January issue of the AIDS.
- Important changes to US prescribing information for efavirenz
- The efavirenz (Sustiva) package insert in the US has been updated to include drug-drug interaction information regarding coadministration of efavirenz with rifampin, diltiazem, itraconazole, voriconazole, atorvastatin, pravastatin, simvastatin, pimozide and bepridil.
- Changes to US product label for T-20 (enfuvirtide)
- On 31 January, the FDA announced that important additions have been made to the product label for T-20 (enfuvirtide, Fuzeon) mainly relating to injection guidance and also use of Biojector (not currently approved in Europe).
TREATMENT ACCESS
- FDA tentative approvals of generic ARVs
- “Tentative Approval” means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, though it may not be marketed in the U.S. because of existing patents and/or exclusivity rights. Tentative approval, however, does make the product eligible for consideration for purchase under the PEPFAR program.
- Wall Street Journal examines reason Abbott increased price of ritonavir
- Previously undisclosed documents and e-mails reviewed by the Wall Street Journal indicate that executives at Abbott Laboratories attempted to “diminish the attraction” of the company’s antiretroviral drug ritonavir (Norvir) by increasing the price of the drug. Ritonavir is used in combination therapies that include drugs manufactured by pharmaceutical companies other than Abbott. According to the documents and e-mails, in the Autumn of 2003 the company “grew worried about new competition to” its antiretroviral Kaletra, and the company’s executives began discussing ways to decrease the popularity of ritonavir with the “goal of forcing” HIV-positive people “to drop the rival drugs and turn to Kaletra,”.
- Access to treatment in the USA: waiting list for ARVs in South Carolina
- At the end of 2006, an article in the New York Times highlighted that more than 350 poor people infected with HIV are on a waiting list for free life-saving drugs in South Carolina, by far the longest such list in the country.
- Royalty-free license granted for development of tenofovir and topical microbicide
- On 11 December, Gilead announced that it has granted royalty-free licenses to develop, and if effective, to manufacture and distribute, tenofovir, used in a topical gel as a microbicide, to the International Partnership for Microbicides, and Conrad.
- Novartis test case in India threatens the ARV “pharmacy of the developing world”
- New Delhi/Geneva, 29 January 2007 - As pharmaceutical company Novartis proceeds with its legal challenge against the Indian government in a court hearing in Chennai today, nearly a quarter of a million people from over 150 countries have expressed their concern about the negative impact the company’s actions could have on access to medicines in developing countries.
- Thailand issues compulsory license to manufacture lopinavir/r: WHO criticised for challenging this essential access to treatment
- On 29 January, Kaiser Daily News reported that Thailand’s Ministry of Public Health had issued a compulsory license to produce a lower-cost version lopinavir/r (manufactured and marketed by Abbott Laboratories as Kaletra).
- Global Fund Board selects new executive director
- The board of the Global Fund To Fight AIDS, Tuberculosis and Malaria announced on 8 February that it has selected Michel Kazatchkine - France’s global ambassador for HIV/AIDS and communicable diseases and a former Global Fund vice chair - to serve as the organisation’s new executive director.
WOMEN’S HEALTH
MTCT
- Response to nevirapine containing HAART following single dose nevirapine for PMTCT
- Polly Clayden, HIV i-Base
- A post hoc analysis from the Mashi study in Botswana [1,2] looked at response to nevirapine-containing antiretroviral treatment among women and infants who had previously been randomised to receive a single dose of nevirapine or placebo as part of a PMTCT strategy [3]. All women also received AZT from 34 weeks of gestation.
PAEDIATRIC TREATMENT
- WHO paediatric recommendations
- Polly Clayden, HIV i-Base
- Following an expert consultation in October 2006 WHO has produced new recommendations on the use and development of antiretroviral medicines for children and infants in which they state: “There is an urgent need for affordable, safe, quality ARV formulations appropriate for paediatric use, particularly solid fixed dose combination (FDC) formulations to facilitate programming planning, improve adherence and facilitate scale up of HIV care for children, in line with a public health approach.”
- Masking the flavour of antiretrovirals in Thai children
- Polly Clayden, HIV i-Base
- In Thailand, 5,000 children (of 50,000 HIV positive children) are now receiving antiretrovirals (ARVs). The formulations of ARVs produced by the GPO were, until recently, mainly solid dosage forms for adults with only a few liquid dosage forms suitable for children. Children have largely received divided adult formulations.
HCV COINFECTION
ONCOLOGY
- Elevated risk of lung cancer among people with AIDS
- Svilen Konov, HIV i-Base
- Lung cancer risk has been estimated to be two to seven times higher in HIV-seropositive people than in general population. Both prognosis and survival in this group are extremely poor. Several studies looking at the smoking habits of the HIV-seropositive individuals in the US and comparing them with the habits of the HIV-seronegative population attempted to find an explanation for the elevated risk, but the results were quite contradictory, mainly as a result of the fact that the studies included only a small number of cancer cases.
PREVENTION
- Two Phase III HIV microbicide trials stopped due to increased transmission
- On 1 February 2007, the International AIDS Society (IAS) issued a press release to the halting of two large Phase III studies of the HIV microbicide candidate Ushercell. Ushercell is a cellulose sulfate based topical gel that was being developed for HIV prevention in women by Polydex Pharmaceuticals.
This information is designed to support, not replace, the relationship that exists between you and your doctor.
©1980-2007. AEGiS.