UK-CAB 24 – Meeting report

BHIVA 2007 clinical audit — microbicides — PEPSE — PrEP — Pfizer

25 January 2008

Summary

There was useful feedback from recent conferences. Key items:

  • Data showing the benefit of starting treatment earlier (with CD4 higher than 200).
  • Equivalence of atazanavir/r and lopinavir/r (Kaletra).
  • Surprising increased risk of heart attack with abacavir.
  • Impact of long-term ARV usage on bone density.

Results from the BHIVA audit were reviewed. These showed that late presentation continues to be a problem, and that resistance testing prior to ARV therapy is not always being done.

Pfizer gave a general overview of their drug development process, highlighting the use of complex 3D chemical models in the discovery process.

An overview on the current state of development in the area of microbicides was given, highlighting the lack of funding, and the continued need for development in this area.

Updates on post-exposure prophylaxis after sexual exposure (PEPSE) and pre-exposure prophylaxis (PrEP) were also given.

Contents

1. UK-CAB updates and conference feedback
2. BHIVA 2007 audit: treatment of naïve patients
3. Pfizer: the drug development process
4. Campaigning for microbicides
5. Promoting PEPSE: what is the role of HIV treatment advocates?
6. Pre-exposure prophylaxis (PrEP).

1. UK-CAB updates and conference feedback

Report on UK-CAB funding, website development – feedback from CROI.

Ben Cromarty, UK-CAB Chair stated that the Steering Group has recently applied for and been awarded funding from The Monument Trust for the period 2008-20011. In addition to allowing the quarterly meetings to continue, this would permit recruitment of a coordinator for UK-CAB. This person would deal with the administrative and operational aspects of the organization. Full details will be circulated in due course.

A new method is being created for the UK-CAB members to communicate. The new web-based system would be more flexible than the current email-based one, as each member would be able to choose what they would be interested in receiving. Members would also be able to choose whether or not they want to be part of certain discussions. It would be a modern, straightforward and intuitive system.

Simon Collins gave some feedback from CROI:

Benefits of continued treatment and earlier treatment: Generally, many studies are showing an overall benefit of treatment, and that there may be benefits from starting treatment earlier than is currently recommended.

Results from the SMART treatment interruption study showed that people had fewer serious illnesses when on treatment with an undetectable viral load compared to not being on treatment. Importantly, this was even at high CD4 counts above 350 cells/mm3.

One presentation from SMART showed that people who restarted treatment in this trial closed the gap between risk of serious infections compared to continuous treatment. This confirmed that the researchers made the right decision to stop the trial early. The same presentation showed that even 18 months after restarting treatment, CD4 counts were still significantly lower than when the trial started – by about 100 cells.mm3.

Results from the SMART trial and current treatments being generally more tolerable are two reasons that the UK guidelines are likely to change to recommend starting at 350 rather than 200 cells/mm3.

Atazanavir/r vs. lopinavir/r (Kaletra) in treatment-naïve patients A large (almost 900 patients), randomised, international study (CASTLE) compared atazanavir/r to Kaletra (lopinavir/r) and found both drugs had similar results in people using treatment for the first time. Atazanavir had less impact on cholesterol. Tenofovir + FTC were the background nukes.

Until now, atazanavir/r has not been approved in Europe for first-line therapy, even though doctors have sometimes prescribed it. As a once-daily drug, this will be a new important option in treatment guidelines.

Side effects: abacavir and risk of heart attack: The large prospective D:A:D cohort study (33,000 patients followed for an average of 7 years) reported current (or recent) use of abacavir was linked with an additional 90% increased risk of cardiovascular disease (heart attack). The real ‘absolute’ effect was most significant in people who had the highest underlying risk for heart disease. This finding generated a lot of discussion because this is the first time this has been reported.

Heart disease is complicated because many factors can contribute to the risk of a heart attack. These include things you can change such as diet, smoking, exercise and lipids (cholesterol levels). Being a current smoker increases your risk by 200-300%, for example. They also include things that you can’t change such as age (risk increases as you get older), gender (risks are higher in men), family history and personal medical history.

It is easy for you or your doctor to calculate your risk of heart disease using an online Framingham calculator. You enter information about your age, gender, smoking status, blood pressure and cholesterol online and press a button. It only takes a few minutes and is recommended for every patient. Based on these results and your individual treatment history, you and your doctor can decide on whether using alternative treatments are important.

A Q & A sheet on these results was produced by the investigators (available on the i-Base site).

Side effects: aging, bone disease: There was a plenary session on HIV and aging that included a good overview by Bill Powderly. One aspect he included was bone health – highlighting that reduced bone mineral density is much lower in HIV-positive people. We have much higher rates of osteopenia (no symptoms, not treated) and osteoporosis (symptomatic, treatable) than the general population. As bone problems increase with age, many researchers and advocates are concerned that bone health is not routinely monitored in most patients.

The session also included a presentation from Charles Flexner, suggesting that older people may get better responses from treatment (and potentially more side effects?) because they clear drugs more slowly, and therefore achieve and maintain higher drug levels.

New medications: There are always studies at CROI about potential new drugs. Many of these are in very early stages of development. Generally, the most important new drugs have either just been licensed or are already available on special programmes in the UK (raltegravir, etravirine, darunavir and maraviroc).

One presentation on a new NNRTI called rilpivirine (TMC-278) looked at whether this could be given by a once-monthly injection. This is very interesting but probably won’t be an option for several years.

Vaccine research: Vaccine news was depressing but realistic. Two main lectures provided a very frank account of why a vaccine is unlikely for many years, if at all.

And a cure? On the cure front, there was a very interesting poster about an HIV-positive man who received a stem cell transplant from a donor who was immune to HIV infection – ie, from someone who had the CCR5 delta-32 deletion. They discontinued his HIV drugs at the same time as they transplant. Two months later, his viral load was undetectable – and has stayed this way (RNA, DNA, in plasma, rectal and bone tissue) for a further six months.

Following this patient for much longer is essential. It is still too early to make very much from one case. Even so, viral load is usually very responsive to absense or presence of ARVs, so this is very interesting.

Even if this works it is unlikely to become a treatment with current technology – because of the difficulty of matching donors and the costs and complication of stem cell transplant. But it is an indication of the direction that treatment may go, and it is good to know that researchers are still looking for a cure.

2. BHIVA 2007 audit: treatment of naïve patients

Dr Hilary Curtis, BHIVA clinical audit coordinator, presented BHIVA’s latest clinic audit of treatment-naïve adults starting anti-retroviral therapy (ART). A primary focus of this study was viral load, in an attempt to see how the existing knowledge was being put into practice in clinical care.

The study included participants over the age of 15 starting ART with no previous experience of treatment (naïve) between April and September 2006. The participants were gathered from 133 clinical centres. Data was submitted data for 1,319 patients. 18 were found ineligible and excluded. 11 of the 133 clinical centres did not take part, leaving 1,215 patients from 122 centres for the initial analysis. Out of these, 45 had major discrepancies between initial and follow up assessment. These were excluded from the final analysis. Overall, 1,170 patients were eligible for inclusion in the final analysis.

The viral load outcomes for 1,215 patients included in the initial analysis were:

  • 70% were undetectable, 14% detectable, 6% stopped ART after pregnancy.
  • 826 patients’ viral load were undetectable and 170 patients’ ware detectable (including patients stopping ART at the end of pregnancy).
  • 68 patients stopped ART after pregnancy, which included 2 with a baseline CD4 count that was less than 200.
  • 151 patients’ outcome data was not reported.

Among patients who started ART with late presentation (CD4 less than 200), 70% were recently diagnosed (less than 6 months previously). There was also delayed treatment among diagnosed patients. 7% diagnosed more than 6 months previously started ART with CD4 less than 50. 36% started at CD4 51-200.

72% had resistance testing data available when starting ART. Of these, 93% showed no resistance. 6% showed single-class resistance. 1% multi-class resistance.

801 patients out of the 1,215 patients were still on HAART after 150 days after starting the treatment. Amongst this subgroup, 84% had undetectable viral load.

The conclusion of the audit was:

  • Outcomes were good across all sizes of treatment centre.
  • Late presentation continues to be a problem.
  • It is a concern that 40% of patients with known HIV infection delayed starting treatment until their CD4 count was less than 200.
  • Starting ART at a low CD4 count was associated with poorer outcomes.
  • A significant proportion of patients were not tested for resistance before starting ART.

Q: When to start ART is key – is BHIVA looking into the reasons why there is late start in treatment?
A: This might be done in the 2008 study. The focus is on TB and how clinics get advice on how to treat complex patients.

Q: Could guidelines for CD4 count and when to start the treatment have played a part here – were patients put off starting treatment?
A: We don’t know the reasons, and it is difficult to get to the bottom of this.

Q: Why spend money on resistance tests, when most people are not resistant?
A: It is part of the guidelines that have been set and therefore should be done. When monitoring the HIV testing through looking at data of years ago, people testing then had resistance, but comparing it with current HIV testing, less people have resistance. There is also a risk of driving worst resistance, if the tests are not being done.

Discussion: Hillary Curtis mentioned that it is important for qualitative research to be done, so that in-depth reasons can be ascertained for why some people start late and others early. It could be that there was a long period of non-attendance between getting tested and starting ART, which could be the result for people starting late.

3. Pfizer: the drug development process

Catherine Burt, a computational chemist, outlined the process of research and development by the pharmaceutical industry in developing a new medicine.

Pfizer, a pharmaceutical company, chose the life cycle of HIV and the development of ART, to illustrate how a drug is developed. An overview of the life cycle of HIV was given to show which parts of this process are targeted with ARVs.

Drug discovery process works in stages:

  • Finding a biological target
  • Screening compounds
  • Lead stage
  • Candidate stage
  • Developmental stage

Using computer programmes, models are created to suggest the biological targets that can be hit. Compounds are screened to get a list of lead compoundss This is done with computational studies. Around 1 million compounds may be screened to get one lead. A huge amount of research goes into this process. Scientists and biologists examine different receptors to observe which ones they can target in the process of an HIV cell infecting the human cells. It could take up to 2½ years to turn an original lead into a candidate drug.

During all these stages, lead compounds are being tested against a pre-set profile. Biologists need to find modules and modify compounds to meet this profile. Modification includes the predicting and testing side effects, toxicity etc that could be caused by certain molecular properties.

Q: What are the programmes they use for studies and projects and creating screening?
A: There is special software for creating graphics of molecules and viruses. Pfizer has software developed in-house.

Q: When are targets being created?
A: During the very early stages. As a pharmaceutical company, we need to patent early, so that if another company finds the same drug they would not get recognition.

4. Campaigning for microbicides

Eunice Sinyemu, African and Minority Ethnic HIV Project, HIV Scotland and Toju Cline-Cole, THT presented the work of the UK African Microbicides Working Group, the current state of microbice research and why microbicides are important.

A microbicide is any substance, whether in a gel or cream form, that can substantially reduce the risk of acquiring or transmitting sexually transmitted infections, including HIV, when it is used in the vagina or rectum. Microbicides do not exist on the market yet, and are still being researched.

The first generation of microbicides could be available in certain countries by 2010. First-generation microbicides include products that work by forming physical barriers to the virus and by changing the chemistry of a woman’s vagina to make infection less likely. These products are formulated into a gel to be applied vaginally just before sex and are therefore coitally dependent.

A second generation of microbicides is also being developed. These typically contain an antiretroviral product that is specific to HIV, unlike first-generation microbicides. These microbicides are being tested in a variety of intravaginal forms – gels, creams, rings, or films – and can be applied once a day, or in case of the ring, once a month. Second generation microbicides are coitally independent. Some may also be a form of contraceptive, where women can be protected from disease and pregnancy at the same time, but non-contraceptive microbicides will also be available.

Microbicides would be available for HIV negative and positive people and some would be able to neutralise pathogens in both semen and vaginal secretions.

One challenge that scientists are being faced with is the developing of rectal microbicides. Rectal microbicides are more challenging, because the rectal cavity is not closed and would require more product to protect the rectal walls. Rectal tissue is also more fragile than in the vagina, because it is thinner and populated with cells that are especially vulnerable to infection. The International Rectal Microbicide Working Group is currently researching the development of rectal microbicides for both heterosexual and homosexual couples.

  • Microbicides would not eliminate the risk of infection, but reduce the risk of infection.
  • The first generation microbicides is only likely to be 40-60% protective against HIV. The second generation may be 60-80% effective.
  • Microbices may offer couples a more intimate option in long-term relationships, where condoms usually exit the scene when trust enters the relationship.

The products now in research fall into four basic categories (known as “mechanisms of action”).

The first approach is to build or improve what the body already does to protect itself. Some candidate microbicides build on the simple principle of maintaining the vagina’s natural acidity, which makes it inhospitable to invading pathogens like HIV, even in the presence of semen. Surfactants disable the virus by breaking up its surface membrane.

Contraceptive microbicides can also disable sperm in the same way so they are strong enough to disrupt invading pathogen, but without damaging the healthy cells that line the vagina wall.

Entry inhibitors work by interfering with the virus getting into the body’s white blood cells, which is the target cell of the HIV cell. Attachment inhibitors prevent attachment of the virus to the white blood cell and fusion inhibitors prevent HIV from actually entering the cell. The last approach is microbicides that are created by reformulating the same antiretroviral drugs developed to treat HIV positive people. These drugs are designed to stop HIV from replicating. The first microbicides to become available may operate with one of these mechanisms of action, whereas the later microbicides may be a combination of two such mechanisms.

Drug development takes years and has to go through a series of phases before it could bridge the gap of being tested on humans.

  • Phase 1 is safety trials, where small number of people at low risk test the product and are monitored for signs of problems.
  • Phase 2 trials gather extended safety data among different groups of people, who may already be HIV positive or have any other opportunistic infections.These two phases are the most crucial for if it is shown to be safe, it can than be tested for effectiveness.
  • Phase 3 can take several years, because many people need to be enrolled to see if the product reduces the risk of HIV.

For phase3 to take place, the country must have a high incidence of HIV, a stable population so that participants could be followed-up easily, and almost no injecting drug use or other sources of HIV risk among women. The majority of effectiveness trials are taking place in Africa.

There are more than 30 product leads under development. 12 of these are currently in clinical trials. 3 are in phase 2 (safety) and phase 3 (effectiveness) trials.

  • Women recruited for effectiveness trials go through a careful informed consent process in their own language and are tested for HIV and OIs.
  • Only HIV-negative women can enrol because scientists needs to see how well the product helps them to remain negative.
  • Women receive condoms and prevention services plus the experimental microbicide gel or condom sand prevention services plus a placebo gel that looks just like the drug being studied but does not contain the active ingredient.
  • To secure safety amongst these women, an independent data safety monitoring board (DSMB) monitors the trials for any concerns that suggest the trial should be stopped.

Presently, no major pharmaceutical company is investing substantially in microbicide research and development (R & D).

Drug development is a complex and expensive process, normally undertaken by large, well-funded pharmaceutical companies. These companies are some of the most profitable enterprises in the world. Large pharmaceutical companies have generated many important, life-saving drugs – including ARVs. But often people need drugs or devices that are not profitable for the pharmaceutical industry to develop. In such cases, the market fails and government and donors must step in to ensure that the public interest is served.

Despite repeated efforts to engage their interest, no major pharmaceutical company has yet invested in conducting its own microbicide R & D.

A few companies (Merck, Bristol Myers Squibb, GSK and Gilead) have released compounds already on their shelves to the International Partnership for Microbicides and agreed to let the IPM test these compounds to see if they are viable candidates microbicides. But these companies retain the license on these compounds and will be able to take them back if they prove viable.

Given the lack of involvement of ‘Big Pharma’, the task of development has fallen to non-profit research institutes, academic scientists and small biotech companies – all of which depend on government grants to move their leads forward. Major pharmaceuticals remain reluctant to get involved because of concerns about scientific and regulatory uncertainty and competing opportunities to invest in products that are potentially more profitable.

In 2000, roughly $65 million was being invested globally in microbicide research, development, testing, policy and advocacy. The vast majority of investment was then, and still is, provided by governments and the philanthropic sector.

By 2004, global investment had more than doubled to $142 million annually, due to sustained activism and growing scientific promise. About 87% of this is from the public sector, and 13% from philanthropic organizations (principally the Bill Gates Foundation).

Projections developed by the International Partnership for Microbicides, the Alliance for Microbicide Development and the Global Campaign for Microbicides estimate that the global annual investment to ensure timely development of a safe, effective microbicide must re-double to at least $280 million per year over the next five years. It must remain at approximately $280 million a year until microbicides are licensed.

The $280 million estimate assumes that:

  • $130 million a year is needed for research (discovery and pre-clinical development)
  • $120 million a year is need for clinical trial site development (for 5 years only)
  • $10 million a year is needed for advocacy and policy (this represents more than a tripling of the annual investment in this category)

These figures do not include any funding for purchase or distribution of a microbicide once it is licensed. This will be an additional cost. According to the Tufts Center for the Study of Drug Development, the average cost in private industry to develop a new drug, including failures, is $802 million.

Q: What is causing the delay in funding?
A: Currently it is taking a long time, because funders feel that the product might fail.

Q: How is UK Funding coming along?
A: At the moment, UK is funding a very large amount.

Q: Is it not safe and best for both parties in the relationship to be aware that the other one is using the microbicides?
A: Some women do not have a choice in whether they want to have intercourse, even if it is with their husbands. Currently in Kenya, many women are being raped, as it is being as a weapon of war, and in an incidence likes these, if microbicides were available, many would be protected from infection.

5. Promoting PEPSE: what is the role of HIV treatment advocates?

Elias Phiri, THT, presented on post-exposure prophylaxis for sexual exposure (PEPSE). The presentation was directed at HIV advocates and how they promote PEPSE. PEPSE is a treatment that involves taking ART, for three weeks if you think you may have come into contact with HIV – for example by having unprotected sex or if a condom broke. This treatment is not 100% effective.

evidence that PEPSE might work:

  • Biological models suggest that HIV takes 3 days to reach lymph nodes and 5 days to reach blood cells.
  • Mother to child transmission studies show that HIV transmission is reduced if a baby is given ARVs.
  • Occupational post-exposure prophylaxis studies show an 80% reduction in healthcare worker infection if AZT is given after occupational injury.
  • Animal models of reduced HIV transmission after genital exposure and observational studies of reduced HIV transmission after PEPSE.

There is still significant ongoing HIV transmission with the UK and PEPSE is seen as a potential method of HIV prevention. There is an increasing demand for PEPSE.

Currently PEPSE is available at GUM Clinics, HIV Clinics, GPs experienced in treating HIV and A+E departments. Guidelines already exist for using and prescribing PEPSE because of the risk of sexual exposure and occupational exposure. Before guidelines existed, people were already requested it.

Key points in guidelines are:

  • When to give PEPSE?
  • What to give?
  • How long to give?
  • Clinical management and follow-up.

When to give PEPSE: The sooner the person receives the treatment, the better. PEPSE needs to be given within 72 hours. PEPSE has proven to be the most effective if given within 24 hours.

What to give: Initially, regimens that were offered in the UK were AZT/3TC + nelfinavirr. This has changed to tenofovir, FTC + Kaletra. The side effects associated with PEPSE are all known to be short-term. Diarrhoea, nausea, headache and vomiting are all known side effects. Side effects reasult in 1 in 5 people to giving up the treatment. Long-term side effects are rarely seen but liver problems, lipodystrophy, heart disease and diabetes are seen.

How long to give: PEPSE should be given for 28 days.

Clinical management and follow up: Pre-PEP: baseline HIV testing, source testing and STI screening. During PEPSE: regular management of side effects, adherence support and a follow-up of source testing. Post-PEPSE (after receiving the treatment): HIV testing at 3 and 6 months, and thereafter risk-reduction management.

The role of advocates is to promote awareness amongst Africans and gay men about their right to receive PEPSE, and working with healthcare staff to increase and improve access to increase awareness.

Thorough training around PEPSE and sexual risk is needed for clinics, hospitals, private practices and telephone helplines. Ways of promoting PEP information are websites, training, workshops etc.

Even though awareness of PEPSE is important, another challenge is funding: if there is a higher demand for PEPSE, where would the funding would come from?

There are debates about the cut-off time for starting PEPSE and about risk assessment if the person arrives later than 72 hours.

6. Pre-exposure prophylaxis (PrEP)

Gus Gairns, a freelance journalist, gave an update on pre-exposure prophylaxis (PrEP). Pre-exposure prophylaxis is giving an HIV-negative person an antiretroviral drug in order to prevent HIV infection.

Before a patient starts PrEP, it is necessary to go for a viral load test. PrEP is necessary partially because of the uncertainty about microbicides (acceptability, liability concerns, rectal use, adherence etc) and also because vaccine trials with the most effective candidates have failed. Now scientists have to go on to the 3rd generation vaccine trials, which will take years for the final product to be released.

The advantages of PrEP are that it is already available, could be taken well in advance, not obvious when used, is user controlled and the safety data, which is of utmost importance, already exists. Under disadvantages are acceptability (to HIV-negative and positive peoples), access to ARVs, non-use of condom and the need for viral load testing if resistance has to be avoided.

Tenofovir is the main drug being used for PrEP. This is because it is the only drug that has been tried an with has an acceptable saftey profile. Nevirapine has been tried but too many side effects. But tenofovir has a high rate of kidney damage and can worsen pre-existing kidney disease. A study showed Truvada (tenofovir + FTC) was a better drug to use and less is needed compared to tenofovir alone.

Many PrEP trials have been performed.

In babies, there are results from the SIMBA trial. 405 HIV positive women were given AZT + ddl from 36 weeks of pregnancy to 1 week afterbirth. When the babies were born, they were given 3TC or nevirapine from birth till 4 weeks after weaning. The results showed that late transmission rate was only 1% and transmission rate during birth was 6%. This compares with 9-10% untreated late transmission rates.

In Ghana, a medium size trail was performed on 371 women. 6 out of 368 controls became HIV positive. 2 out of 363 who took tenofovir became HIV positive. Statistically, the trial was not significant because it was too small.

Many trials are still running:

  • Results from a trial in Thailand on drug users, using tenofovir: results due in 2008.
  • Botswana high-risk heterosexuals using Truvada: results due in 2009.
  • Peru/Ecuador gay men/MSM using Truvada: results due in 2010.
  • Small safety trial of gay men in San Francisco, Atlanta and Boston: results in 2009.

Many trials have been abandoned. Rreasons include political controversies (eg in Cameroon during 2006, the biggest issue being compensation for seroconverters).

There was still uncertainty about what PrEP trials were about among participants, and major ethical dilemmas. One of these issues was the perception that Gilead was only using PrEP to sell more tenofovir and that participants believed that PrEP was a vaccine and so condoms were unnecessary.

If PrEP trials were to succeed, cost would be a major consideration. PrEP would only be cost-effective in high-risk populations.

Q: Does PrEP mean there can be a reduction in the amount of drug used?
A: If there is a positive reply from the trials, then the next one would use a decreased amount of drug an examine the outcome.

Q: If you missed a pill, would your chance of being infected be high?
An: It is the same as any drug, it will increase your chances of infection and resistance is also something that needs to be considered.

Q: What are some of the disadvantages?
A: Testing for viral load before PrEP – effiectiveness cannot be assured.

Q: How does one sell a trial where 100% condom use would mean the trial failed?
A: The same way you sell a vaccine trial where HIV incidence continues.

Attendees

Salima Adatla, Royal Free Hospital, London.
Florence Akoshile, independent, London.
Zhana Books, independent, London.
Gus Cairns, freelance journalist, London.
Liz Carey, The Our Project, Bradford.
Jabulani Chwaula, THT, London.
Paul Clift, independent, London.
Toju Cline-Cole, THT, London.
Ben Cromarty, North Yorkshire AIDS Action, Northallerton.
Richard Day, Yorkshire Mesmac, Bradford.
John Holland, Feedback South London, London.
Robert James, UK-CAB, Leeds.
Pamela Kaseke-Mushore, CAN, London.
Mary Lima, THT, London.
Svilen Konov, HIV i-Base, London.
Michael Marr, Waverley Care Solas, Edinburgh.
Joe Murray, National AIDS Trust, London.
Roger Pebody, THT, London.
Elias Phiri, THT, London.
Rachel Ruschombe-King, Avert, Horsham.
Jax Shapter, Mainliners, London.
Eunice Sinyemu, HIV Scotland, Edinburgh.
Gemma Spink, Avert, Horsham.
Martin Ward, THT, London.
Matthew Williams, The Monument Trust, London.
Godwin Yomi, THT, London

Speakers

Dr Hilary Curtis, BHIVA clinical audit coordinator.
Eunice Sinyemu, African and Minority Ethnic HIV Project, HIV Scotland.
Toju Cline-Cole, THT.
Elias Phiri, THT.
Gus Cairns, freelance journalist.
Catherine Burt, computational chemist, Pfizer.

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Published: January 24, 2008
Last edited: December 19, 2010