UK-CAB 21 – Meeting Report

African treatment issues — Merck

20 April 2007
Programme for the meeting
Reading material

Post Meeting Report

1. Feedback from CROI 14
2. Integrase Inhibitors – Merck
3. Introduction to genetics – Simon Collins
4. The impact of genetic differences in treating people of african origin – Charles Mazhude
5. Community Slot at BHIVA Conference – Gus Cairns
6. AoB and next meeting

Members attending

Elijah Amooti
The African Eye Trust

Mercy Banda
UKC

Jabulani Chwaula
THT

Paul Clift
UKC

Ben Cromarty
North Yorkshire AIDS Action

Yvonne Feare
Zimbabwe Women’s Network

Richard Jackson
THT West

Robert James
UK CAB

Mohamade Jowata
Brent PCT

Pamela Kaseke-Mushore
UK CAB

Mohammed Kikambi
ACIA

Svilen Konov
i-Base

Mary Macarau
Kensington and Chelsea PCT

Michael Marr
Waverley Care

Tuli Matheus
The African Eye Trust

Janet Murunji
The African Eye Trust

Simon Mwendapole
Uganda AIDS Action Fund

Viola Nakayenga
UKC

Tendai Ndanga
Positively Women

Maureen Ndawana
Zimbabwe Women’s Network

Tarsisio Nyatsanza
Waverley Care

Kingsley Oturu
Queen Margaret University

Roger Pebody
THT

Elias Phiri
AAEGRO

George Rwamakuba
AHEAD

Winnie Seruma
The African Eye Trust

Kapulu Simonde
Waverley Care

Jax Shapter
UK CAB

Jack Summerside
UKC

Carmen Tarrades
ICW

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Introduction:

The chair (Badru Male) welcomed the participants

1. Feedback from CROI 14

1.1 New drugs – Simon Collins

CROI 2007 was the 14th Annual Conference on Retroviruses and opportunistic Infections, held in Los Angeles, 25-28th February 2007. This annual US conference is the largest scientific forum on HIV, and unlike other conferences that include other issues, CROI focuses almost mostly on science, with less input from pharmaceutical companies. This year, there were a number of important developments in new drug areas. Details can be found in the pre-reading material on the website: Feedback from 14th Conference on Retrovirus and OIs

1.1.1 Raltegravir (MK-0518)

The results of two trials called BENCHMARK 1 and 2 were presented for this new class of drugs-Integrase Inhibitors (II). They target the integration step of HIV replication, in which viral genetic material is inserted into the DNA of human cells. By blocking this step in the viral life-cycle, researchers hope that IIs will prevent the virus from reproducing and infecting more cells.

The trial was for treatment experienced patients with three-class resistance, and compared an Optimised Background Therapy (OBT) to a regimen including the new Merck II, Raltegravir (RGV).

At 16 weeks, the results were extremely encouraging, showing much higher levels of viral suppression in the arm of the trial using RGV: 77% achieved a viral load (VL) of less than 400 copies compared with 40% in the placebo arm, and 60% less than 50 copies compared with 34%.

In addition to being highly potent, there appeared to be few problems with side effects from raltegravir. RGV may also be an option for treatment-naïve patients, but further studies will be needed to establish this.

This result, taken with the results for Maraviroc and some of the other new drugs, represents a very exciting development in HAART therapy.

1.1.2 Maraviroc

Maraviroc (MVR) is a CCR5 inhibitor manufactured by Pfizer. Results from 24-week trials comparing MRV with OBT and a placebo showed that more than half of highly treatment-experienced patients achieved a viral load of less than 400 copies.

1.1.3. Rilpivirine (TMC-278)

48-week results from a Phase 2 TMC-278 dose-finding study of a second generation NNRTI in development from Tibotec were presented. The results suggested that the new compound performed as well as efavirenz (EFV) in terms of effectiveness and potency, but with fewer central nervous system (CNS) side effects, and with a slightly better lipid profile.

1.1.4. Eltegravir (GS-9137)

This is also an integrase inhibitor (INI), but manufactured by Gilead. The studies are a bit behind the Merck studies, and the results are not as dramatic as the RGV results, but these were dose-finding trials and future Phase III trials will be of a design, similar to that used by Merck for RGV.

1.1.5 TH9507

26-week results from a Phase 3 study of TH9507, a growth hormone releasing factor analogue (GHRF) produced by Theratechnologies (Canada), in patients with central fat hypertrophy were presented. Over a period of 6 months, a 20% decrease in central body fat was seen. This is an impressive result; however, use involves an injection a week, and there was quite a high dropout rate from the trial, with a fairly high degree of adverse effects. Nonetheless, the level of unacceptable side effects was less than that seen in similar trials using recombinant human growth hormone (rHGH).

1.2 Other topics – Gus Cairns

1.2.1 MDR-TB

There seems to be a failure of health systems around the world to pick up on the issue of multiple drug resistant (MDR) TB. In many parts of the world, it appears that there are parallel health systems – an old one for TB, and a new one for HIV, and the two don’t always talk to each other. Only 7% of those with TB were tested for HIV, but it is likely that the numbers of those co-infected will be much higher. There is also concern about extremely drug resistant (XDR TB), which is on the rise and which is virtually untreatable in the developing world.

1.2.2 Breastfeeding or Formula for mothers with HIV?

There were a number of presentations on this topic. It would appear that in some resource-poor settings the benefits of breastfeeding might outweigh the (high) risk of HIV transmission from breastfeeding. However, this is a case of bad and worse; the mortality rate of formula fed babies can be high, sometimes due to contamination of the water supply; but breastfeeding to raise the survival rate will probably lead to HIV transmission, and mortality later without HIV treatment.

1.2.3 Malaria

Providing HIV-positive children in Uganda with insecticide-treated bed nets (ITNs) and cotrimoxazole (Septrin) prophylaxis (CTX) dramatically reduced their risk of acquiring malaria, according to results from the CHAMP (Children with HIV and Malaria Project) in Kampala.

1.2.4. Prevention Studies

There was feedback from a number of trials, though human-based studies are still some years away. There were some promising studies of anal microbicides using tenofovir (TDF) in monkeys. A different microbicide trial using cellulose sulphate in humans, which appeared to be promising, had to be stopped due to significantly more women on the microbicide arm being infected with HIV. The reason for this is not yet known, but appears to be localized to one site.

Results of PrEP (pre-exposure prophylaxis) were somewhat discouraging, in that it appears that dosages need to be similar to those taken as a component of HAART, and need to be taken regularly.

Studies showed that circumcision was effective at reducing the transmission rate of HIV for men, and there was some discussion about the need to publicise this and advocate it as a means of reducing the spread of the epidemic.

1.2.5. HPV

There were results showing that smoking increases the HPV viral load and increases the risk of cervical cancers.

1.2.6 Infection models

It has long been suspected that a lot of HIV infections arise from the period of early infection. Some modelling studies in Quebec suggested that about 50% of infections are acquired from people who have been recently infected themselves. This has been supported by other studies and is based on the extremely high viral load levels that occur in the first few months after infection. This presents a prevention challenge, since people who are themselves only recently infected are the people least likely to know that they are positive, and current HIV testing does not pick up individuals who have just been infected.

1.2.7 Acyclovir

HIV and the Herpes virus appear to be cross-related to some extent. The use of aciclovir has been previously suggested as an aid to HIV prevention because herpes co-infection, particularly if it is symptomatic, appears to increase the risk of both HIV acquisition and of transmission 2-5 fold. Results from studies were disappointing, though, showing only slight reductions in VL.

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2. Integrase Inhibitors – Merck

There was a presentation on the topic of Integrase Inhibitors by Merck. Present from Merck were:

Paul Robinson
Lee Robson
Linda Brown
Helen Wright

A brief introduction to how HIV operates, and how IIs work, was given. This can be seen on the Merck website (www.benchmrk.com) as a video. Results of the most recent trials were presented at CROI, and have also just been published in the Lancet, but Merck were not yet able to let us have a copy of the slides used. As soon as they are released, they will be put on the UK-CAB website. Details of the trials and the results are given below, courtesy of Aidsmap.

Participants in the BENCHMRK studies were resistant to all three major classes of antiretroviral drugs and had viral loads above 1,000 copies/ml. They were randomised on a two-to-one basis to receive either 400 mg raltegravir twice daily or placebo, in addition to optimised background therapy. The primary outcomes were the proportions of patients achieving viral loads below 400 and below 50 copies/ml. Data were also gathered on changes in CD4 cell count and drug safety.

Baseline characteristics were similar in the raltegravir and placebo arms of the two studies. The mean age was about 45 years, most (84-91%) were men and a majority (55-81%) was white, though BENCHMRK-2 included more people of other races/ethnicities. The mean baseline CD4 cell count was between 146 and 163 cells/mm3 and the mean baseline viral load ranged from about 30,000 to 50,000 copies/ml. About 90% had an AIDS diagnosis and the median duration of antiretroviral therapy use was about ten years.

Results from 16 weeks of follow-up were presented for all participants in the two studies, although the investigators noted that 24-week results are available for approximately 60% of patients. Both studies are scheduled to continue through 48 weeks.

After 16-24 weeks, approximately twice as many patients in the raltegravir arms achieved undetectable viral load. In the two studies combined, 77% of participants taking raltegravir had HIV RNA levels below 400 copies/ml, compared with 41-43% in the placebo arms (p < 0.001). Looking at viral loads below 50 copies/ml, the corresponding figures were 61-62% and 33-36% (p < 0.001).

Gains in CD4 cell count were also more impressive amongst the patients who received raltegravir, with a mean increase of 83 cells/mm3 in BENCHMRK-1 and 86 cells/mm3 in BENCHMRK-2. These gains were 2-3 times as large as those seen in patients who received placebo plus optimized background therapy (p < 0.001).

Researchers also presented data from analyses of patient subgroups, again combining data from both studies. Amongst those whose background regimens included both enfuvirtide (Fuzeon) or the newest protease inhibitor, darunavir (Prezista) – to which HIV is less likely to be resistant — 98% in the raltegravir arm achieved viral suppression below 400 copies/ml, compared with 87% in the placebo group. This compared with rates of 74% and 29%, respectively, for patients not taking either of these newer drugs. For patients who had no other active drugs in their regimens, 61% in the raltegravir arm, but only 5% in the placebo arm, achieved HIV RNA levels below 400 copies/ml. In addition, participants who started with lower baseline viral loads or higher baseline CD4 cell counts had a better response to raltegravir

Raltegravir was well tolerated overall, and only a small number of participants discontinued the studies early. Side effects – mostly mild-to-moderate – were seen with similar frequency in the raltegravir and placebo arms. The rate of serious drug-related adverse events was less than 3% across all arms.

Three times as many patients experienced virological failure on placebo compared with raltegravir (16% vs. 51%). Though data are still limited, it appears that there are two distinct pathways that confer raltegravir resistance: N155H and Q148K/R/H. However, there was no indication of cross-resistance with other antiretroviral drug classes.

The researchers concluded that raltegravir demonstrated “potent and superior antiretroviral activity” compared to placebo plus optimized background therapy at 16 weeks, with “few adverse experiences leading to discontinuation.”

Q: When will RGV be available and at what cost?

A: Filing in parallel in the US and Europe in the next quarter or so. Study sites for further trials have been selected (none in Africa). Pricing is being considered but has not yet been determined.

Q: Some patients became resistant to RGV very quickly – why? How?

A: About 16% were not responsive, mainly due to resistance. 2 key mutations are needed. It is likely that resistance developed after taking RGV, rather than there being earlier natural mutations (polymorphisms) that were there before people started treatment.

Q: Can you say more about expanded access?

A: In the UK, Merck will use the named patient route. There will be an admin charge of around ‚¬50/day – as for T-20 – with a refund when pricing is cheaper later. In the rest of the world, the expanded access programme will operate, which is a very safe way to proceed.

Q: Are there any interactions or side-effects with Hep C treatments?

A: Based on our current data (on how the drug is metabolised) we have seen nothing that would cause concern.

Q: What are the likely long-term side-effects?

A: impossible to say at this stage. Although the drug appears to be very clean, we can’t be sure. Close monitoring of users over the next few years will be needed.

Q: Is Merck part of the DAD study?

A: Not sure – no objection in principle.

Q: Are there plans for use in naïve patients?

A: Trials are planned but results will not be available until 2009/2010.

Q: is there a paediatric formulation?

A: Studies have just started – nothing yet.

Q: Can RGV be used on pregnant women?

A: No studies have been done. Data are being collected and documented. Animal toxicity results look clean.

Q: How does Merck feel about the Abbott pricing policy in Thailand?

A: As a company, Merck is open to finding ways for improving access to treatment in developing countries. Third party licensing may be a way forward but no decisions have been taken as yet.

Q: Anything else in the pipeline?

A: Merck has an active research programme, with a number of avenues being explored. A recent acquisition of a PI is of interest and may serve as a possible replacement for ritonavir.

Q: Can you say something about the HPV vaccine?

A: The vaccine, Gardasil, is a joint venture between Merck and another company (CSL Ltd. from Australia). It is being marketed and licenced on the basis of prevention of cervical cancer, rather than any form of STI protection, and as such, it will most likely be only made available on the Health Service to girls.

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3. Introduction to genetics – Simon Collins

Responses to treatment may differ in individuals. This can be due to social circumstances such as access to treatment and support; adherence; early/late presentation. However, there may also be genetic differences – either in the virus – different strains of HIV – or in the individual – some people are known to be “slow progressors”, for example. There has not to date been a lot of genetic research done in this area.

Most drug trials and research in the HIV field have been done on Caucasian males; there may be differences seen with other groups, and the relevance of the research data needs to be tested when possible.

Some specific examples have been found to date:

A couple of years ago there were several studies that showed that a genetic variation that was more common in African patients, was also related to how NNRTIs are metabolised. The genetic change is in one of the liver enzymes responsible for drug metabolism (called CYP2B6) at codon (junction) 516. The ‘normal’ structure is to have a guanine (G) base at this junction. When there is a mixture of this G and thymine (T), efavirenz metabolism is slowed, and when there is only thymine at this junction, the metabolism is slowed even further (and drug levels are higher).

The implications of this are:

  • there is a higher risk of side effects for African people using efavirenz, because drug levels can be much higher. This should include taking more care with African patients, and perhaps use of drug level monitoring.
  • that anyone stopping treatment needs to be aware that drug levels continue for weeks afterwards, especially long after any other drugs have been completely eliminated. This would increase the risk of developing drug resistance. The recommendation in BHIVA guidelines (not addressing African patients specifically) is to either stops nukes 1-2 weeks earlier or to switch to a protease inhibitor for the last few weeks. The results suggest that switching to the PI is probably best, and doing this for 4 weeks rather than two may be better for African patients.

2. A severe allergic reaction, characterised by symptoms including fever, rash, stomach problems, lethargy and malaise, occurs in approximately 8% of individuals who start treatment with abacavir. Most individuals who experience this hypersensitivity reaction do so within the first six weeks of treatment with the drug. If treatment with abacavir is stopped after the development of the hypersensitivity reaction, it must never be restarted as this can have potentially fatal consequences.

The hypersensitivity reaction appears to occur less frequently in individuals of African origin, men, and patients with more advanced HIV disease. However, a higher CD8 cell count at the time abacavir therapy is started has been associated with an increased risk of hypersensitivity occurring. Tests also suggest that the presence of the HLA-B*5701 gene is associated with an increased risk of hypersensitivity to abacavir. The distribution of this gene varies around the world and is found most frequently amongst Caucasians in northern Europe, North America and Australia.

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4. The impact of genetic differences in treating people of african origin – Charles Mazhude

This whole area is really still in its infancy. Ethnic labels are not precise and genetics does not equal race. Some “white” people can have some “black” genetics, and vice versa. Genetics is also being used as a tool to study the epidemiology of the HIV epidemic.

There are differences in the way that people respond to HIV infection and treatment. Factors affecting this include:

  • genetics – host characteristics
  • genetics of the virus
  • environmental factors

HIV therapy therefore needs to be individualized. A better understanding of the genetic factors may refine this further in the future.

The human genome is HUGE, with 3 billion base pairs (1 base pair is a “gene”). Genetic analysis is still very time consuming and expensive. Four areas will be addressed in this talk:

  • risk of acquiring HIV infection
  • clinical manifestations of HIV infection
  • HIV progression
  • Pharmacogenomics

Are there genetic factors that are relevant for the acquisition of HIV? It is in principle possible. However, studies in the US in the pre-HAART era suggest that differences in terms of clinical presentations are few, and environmental factors are of much greater importance than genetic ones.

There is one area where there is a key genetic difference: HIV-associated nephropathy (HIVAN) is the leading cause of end-stage renal disease among HIV-positive individuals in well-resourced countries, most of whom are of African descent. However, although HIVAN is clearly linked to African ethnicity, until now information has been severely lacking about renal disease in HIV-infected populations in Africa.

Is there a genetic difference in the rate of disease progression? It has proven difficult to compare studies done in different arts of the worlds in this area. Some recent studies suggest that people of African origin progress to AIDS more rapidly; however, there are difficulties in determining precise dates of infection; study parameters differed; and difference in access to health care make elimination of environmental factors difficult. More recent UK studies suggest that there is no difference in the rate of disease progression for different ethnic groups.

Pharmocogenomics is the study of the genetic basis of individual variations in response to drug therapies. It is relatively new in the area of HIV, but may ultimately allow for more individualization of therapy. It may also increase the ability to predict outcomes – such as the effectiveness of therapy or the likelihood of drug toxicities.

There are some areas in HIV where genetic factors have been found to play a role:

4.1 Efavirenz (EFV).

It is now well known that black patients are more prone to experience adverse CNS side-effects with EFV, and that EFV remains in the body much longer, leading to an increased risk of acquiring resistance of EFV treatment is stopped in an uncontrolled way.

4.2 Nevirapine (NVP)

The NNRTI nevirapine causes rashes in 20-30% of people. This rash is usually mild and disappears as the body gets used to the drug. A steroid called prednisone may be useful in reducing the frequency of rash in people taking nevirapine. Women are at greater risk, but ethnicity does not appear to be a major factor. A high CD4 count (greater than 25%) also appears to increase the incidence of NVP hypersensitivity.

4.3 Abacavir (ABC)

In a small number of cases, a sever reaction is seen which can be fatal. Trials have suggested that there is an ethnic difference here, in that the gene causing the hypersensitivity is less common in black patients.

4.4 Atazanavir (ATZ)

Jaundice (high bilirubin levels) is experienced in some patients. This is more common in black patients.

In conclusion, then, we need to be careful when using the term “African ethnicity” – it is imprecise. Africa is large and diverse; racial mixing is the rule rather than the exception; and we need to consider the genetics, not “ethnicity”.

Ethnic grouping has had limited effect in explaining treatment variations. Differences seen frequently reflect different access to care. HIV drugs seem to work well across all ethnic groups, though some differences in toxicities have been seen. Pharmacogenomics has a potential role in the individualization of HIV drug therapies in the future. Clinical trials should include diverse genetic groups and be sufficiently powered in order to further evaluate this area.

Q: What are the social/political impacts of stigma?

A: Stigma is a huge issue, and a lot of education is needed to remove it. Even in the primary health sector, there is today a degree of ignorance and stigma. If a black African is diagnosed with TB, then often they are assumed to be HIV positive as well. Even if clinically there may be evidence to lead to this kind of conclusion, the matter needs to be dealt with much more sensitively.

Q: Here in the UK, asylum seekers may be moved to second-line treatment therapies due to resistance. However, if they are subsequently deported, it is often to countries where these treatments are not available. Surely this is an argument against deportation?

A: This is a complex issue and not solely a clinical issue – it is also highly politicsed. There are some countries where there may be second-line therapy, and Winnie has some contacts of such groups in Uganda, Kenya and Sierra Leone. However, it may also be the case that despite what is said by the governments involved, once an individual gets to the country, the reality on the ground may be quite different.

Q: What are the top three issues for patients of African origin?

A: late presentation; access to care; research directly relevant to black people on treatment; and stigma.

Q: Are there differences in how long-term toxicities present in different ethnic groups?

A: Metabolic complications can present differently: cholesterol in white men can lead to heart attacks, but in black women, a stroke is more likely.

5. UK HIV Drug Resistance Database – David Dunn

The slides used are available

Drug resistance testing became available in the UK in about 1997-8, and is done in about 12 labs. It is recognized that these test results represent a valuable scientific resource, but is not being well-exploited at present. In 2001, a central repository for these results was set up, overseen by the UK Collaborative Group on HIV Drug Resistance. This includes representatives from labs doing the testing; clinicians; academics; MRC CTU; UCL; UK CHIC; and the HPA. The group would like to have a community representative as well.

There are principles of collaboration, which cover areas such as data confidentiality, access to data, publication policy and so forth. The Steering Group meets every 6 months. A number of papers and abstracts have been produced to date. Funding is an issue, but there is some “bridge” funding in place for the immediate future.

A community rep would need to have some obligations:

  • some knowledge of the science behind resistance
  • an advocate for the struggle with DoH for funding
  • input in the area of confidentiality

The next SG meeting is June 6th; it would be useful to have a rep in place by then.

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5. Community Slot at BHIVA Conference – Gus Cairns

We have a 1-hour slot at the next BHIVA meeting in the autumn on the topic of Electronic Patient Records (EPR), co-owned with BHIVA. The main focus is information for clinicians, but with a patient input. Gus has some ideas for inputs and after the Spring BHIVA Meeting will be moving this forward. Gus is looking for a co-chair from the community.

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6. AoB and next meeting

Next meeting 13 July 2007. Topic-testineg and lab results.

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Published: April 20, 2007
Last edited: December 19, 2010