UK-CAB 23 – Access to treatment for migrants and people facing deportation – Roche

2 November 2007

Programme

Background reading

GEMINI study

Saquinavir/r vs lopinavir/r: interim results from the Gemini study

Results were presented in Glasgow by Slim and colleagues from a planned interim analysis of the first 150/337 treatment naïve patients randomised to either saquinavir/r (1000/100mg BID) of lopinavir/r (400/100mg BID) in a prospective open-label study.

All patients received tenofovir/FTC as background RTIs. The trial is being run in the USA, Canada, Puerto Rico, France and Thailand. The primary endpoint of the study is the percentage of patients with viral load <50 copies/mL at week 48.

The study enrolled 75% men and 25% women. Baseline characteristics were generally balanced between both arms and included mean CD4 count 114 cells/mm3 and viral load 5.1 log copies/mL, median age 36 years (range 20-63), 11% HCV coinfected. There is a slight trend in the lopinavir/r arm for patients to be more advanced compared to the saquinavir arm (40% vs 32% with CD4 counts < 50 cells/mm3; and 37% vs 28% with a prior AIDS defining event).

At week 24, there were 5 virologic failures in the saquinavir group (6.8%) versus 2 (2.6%) in the lopinavir group. 69% of saquinavir/r patients compared to 75% of lopinavir/r patients had achieved viral suppression < 50 copies/ml (p=0.43, NS between arms). Results were 74% vs 84% for ITT <400 copies/mL assay. Mean changes in CD4 and viral load were + 279 vs +294 cells/mm3 and -3.2 vs -3.5 logs copies/mL in the saquinavir/r vs lopinaivr/r arms respectively.

Fourteen patients discontinued saquinavir/r (3 due to side effects, 11 for non-safety reasons) vs 13 with lopinavir/r (4 side-effect s, 9 non-safety). There were no significant differences in Wk 24 efficacy measures.

Fasting lipid parameters were similar at baseline but changes by week 24 favoured the saquinavir arm. Total cholesterol increased above >/= 5.2 mmol/L (grade 1 or higher) in 7.9% patients on saquinavir vs 25% of patients on lopinavir arm (P<0.01); triglycerides increased to over 4.5 mmol/L (grade 2 or higher) in 1% vs 9% lopinavir/r patients (P<0.05).

Comment

Although this data is interesting, we need to wait for full 48-week analysis in order to see whether some of the small differences between the arms become more significant by the end of the study, and for a full comparison of the safety profile.

The question was also raised in a question after the presentation, about whether interim results should be presented.

As there is little recent data from randomised trials that compares saquinavir/r to other boosted PI-regimens, these results will be important. Results from the MaxCmin2 study, presented as a late breaker at the IAS conference in Paris in July 2003, had a similar design and showed results that benefited lopinavir/r. 2

This study will show whether new formulations of both drugs have any impact on earlier results (Fortovase was used in the MaxCmin2 trial).

References

1. Slim J, Avihingsanon A, Ruxrungtham K et al. PL2.5 Saquinavir/r (SQV/r) BID vs lopinavir/r (LPV/r) BID plus emtricitabine/tenofovir (FTC/TDF) QD in ARV-naïve HIV-1 infected patients: GEMINI Study. 8th ICDTHI, 12-16 November 2006, Glasgow. Oral abs PL2.5.

2. Youle M, Gerstoft J, Fox Z et al. Final week 48 analysis of a Phase IV, randomized, open-label multi-centre trial to evaluate safety and efficacy of lopinavir/ritonavie (400/100mg BID) versus saquinavir/ritonavie (1000/100mg BID) in adult HIV-1 infection: the MaxCmin2 trial. 2nd IAS Conf HIV Pathog Treat 2003 Jul 13-16. Abs. LB23.

http://www.aegis.com/conferences/iashivpt/2003/lb23.html

Boosted saquinavir as good as Kaletra, Gemini study shows

Gus Cairns, Friday, October 26, 200

http://www.aidsmap.com/en/news/31F71894-568A-4D07-8B01-064B61743EC2.asp

The 11th European AIDS Conference in Madrid heard that saquinavir boosted by ritonavir (SQV/r – Invirase) is essentially equivalent in terms of potency to boosted lopinavir (LPV/r – Kaletra) in patients new to HIV therapy.

After nearly a year on therapy (48 weeks) the proportion of patients with an undetectable viral load (below 50copies/ml) was 64.7% on SQV/r and 63.5% on LPV/r.

Viral load suppression by the two drugs was also almost identical, with SQV/r achieving a 3.39 log₁₀ reduction in viral load and LPV/r a 3.36,₁₀ log reduction (about 2500- and 2300-fold respectively). The probability of this result being due to chance was 0.0058 or one in 172.

Lead investigator, Professor Sharon Walmsley of the University of Toronto, was presenting the results of the GEMINI study, which randomised 337 antiretroviral-naïve patients to receive either SQV/r plus tenofovir/emtricitabine (TDF/FTC -Truvada) or LPV/r plus TDF/FTC.

All patients who started the study had CD4 counts below 350 cells/mm3 and viral loads over 10,000 copies/ml. Four out of five were men, with a median age of 38 years. They were in advanced HIV infection: the median viral load at the start of the study was high, at 160,000 copies/ml and the median CD4 count low, at 138 cells/mm3. Sixty-three per cent had viral loads above 100,000 copies/ml and 40% had CD4 counts below 100 cells/mm3.

One hundred and sixty-seven patients started the study on SQV/r and 170 on LPV/r but the 48-week analysis was of 263 patients, 128 on SQV/r and 135 on LPV/r. About 20 patients in each arm were excluded from the final results because of protocol violations (i.e. they should never have been in the study in the first place) and 30 either changed treatment due to failure or toxicity or were lost to follow-up.

In all, 23% of patients discontinued SQV/r treatment and 21% LPV/r. Of these, 5% versus 8% were due to safety concerns, i.e. adverse lab results, and 3% versus 7% were due to adverse events, i.e. symptoms. The proportion who discontinued due to incomplete viral suppression was 9% in the SQV/r arm versus 3% in the LPV/r arm. There were four deaths, three of them in the SQV/r arm.

The proportion with undetectable viral loads at week 48 was about 5% lower than halfway through the study at week 24, when the proportion with viral loads under 50 had been 69.9% on SQV/r and 69.0% on LPV/r.

The increase in CD4 count was 127 at week 24 and 178 at week 48 for patients on SQV/r; it was 134 at weeks 24 and 204 at week 48 for patients on LPV/r. The differences between the two drugs were not statistically significant.

There were eleven failures due to incomplete viral suppression on SQV/r and five on LPV/r. Five of the eleven SQV failures had at least one HIV protease inhibitor resistance mutation at baseline compared with none of the three LPV failures; five of the patients on SQV and four of those on LPV developed the M184V FTC resistance mutation; and one patient in each arm failed virologically with apparently wild-type, non-resistant HIV.

Only one patient, taking saquinavir, developed a new protease inhibitor resistance mutation (in addition to M184V) while on failing therapy, and they were one of the ones with primary PI resistance. Six patients on SQV/r had ‘documented poor adherence’, Walmsley said, versus two on LPV/r.

In terms of side effects, the study tended to favour SQV/r. Seventeen per cent of patients on SQV/r complained of diarrhoea versus 27% on LPV/r.

In terms of lipids, the percentage of patients with total cholesterol above the upper limit of normal went up in both groups, from 14% to 31% on SQV/r and 10% to 39% in patients on LPV/r. However at week 48 34% of patients on SQV/r versus 24% on LPV/r had raised levels of ‘bad’ LDL-cholesterol.

For triglycerides, the proportion with abnormal levels (two times the upper limit of normal) went down in patients on SQV/r from 1.9% to 1.4% but up from 2.4% to 9% in patients on LPV/r.

“We urgently need more HIV treatment options with favourable lipid profiles, which is why I welcome the results from this study,” Sharon Walmsley commented.

Reference

Walmsley S et al. Saquinavir/r (SQV/r) BiD versus lopinavir/r (LPV/r) BiD, plus emtricitabine/tenofovir (FTC/TDF) QD as initial therapy in HIV-1 infected patients: the GEMINI study. Eleventh European AIDS Copnference, Madrid. Abstract PS1/4. 2007.

Biojector

Roche withdraw application for Biojector ‘needle-free’ option for T-20

http://i-base.info/htb/2136

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

The reasons for not continuing with the applications was given as ‘based on comprehensive assessment of the clinical program, as well a significant delay in achieving U.S. regulatory approval due to the time required to generate additional data’.

It has been over three years since the first studies showing similar pharmacokinetics and the potential for better tolerability using Biojector compared to regular injections. 2, 3 Safety concerns in larger studies included an increased risk of nerve damage and haematoma.

Patients in the UK are not able to access Biojector as the manufacturer does not have a European license for this device.

Patients currently using Biojector in the US through an expanded safety trial may be able to continue to use the device, as it is still commercially available there.

References

1. Press release: Roche and Trimeris provide update on development of alternative administration options for delivery of FUZEON: Companies withdraw application to market Biojector® 2000 device for use with Fuzeon. (03.10.07)
http://www.roche.com

2. Needle-free injections for T-20 in the US. HIV Treatment Bulletin, April 2005.
http://ww1.aegis.org/pubs/i-base/2005/IB050604-29.html

3. T-20 studies presented at Rio. HIV Treatment Bulletin, September 2005.
http://i-base.info/htb/7092

See also:

http://www.bioject.com/pdf/improved_fuzeon.pdf 1.1 MB

Deportation from UK based on HIV status

On 5 May 2005 the House of Lords delivered a judgment on the matter of ‘N’ (2005 UKHL31). It ruled that deportation of a person living with HIV to a country where s/he was unlikely to receive adequate HIV treatment was not incompatible with their right to be free of inhumane treatment under Article 3 of the European Convention on Human Rights.

In concluding their written judgment, the Lords made it clear that the Home Office can exercise discretion in deciding not to return such individuals to their home countries, but that if it decides on deportation, it will not be operating in breach of human rights legislation. In the view of a number of HIV advocates, this decision essentially authorizes hundreds of HIV-positive people living in the UK to be deported to their home countries.

Our Position The AHPN believes that there is a clear contradiction between the UK’s policy aim of universal access to HIV treatment for all those who need it by 2010 and the deportation of people living with HIV who are on treatment to countries where treatment is not readily available or affordable. The withdrawal of treatment increases the body’s vulnerability to opportunistic infection and will result in drastically shortened life expectancy.

The AHPN believes that there are strong public health arguments for allowing a concession. Those awaiting removal may go underground and fail to keep appointments resulting in an increased risk of opportunistic infection with the need for emergency treatment and an increased risk of onward transmission. The Department of Health has valued the prevention of one single onward transmission as between £0.5 and £1 million in terms of individual health benefits and treatment costs.

The “Destination Unknown” Campaign is calling on: The Home Office to delay the deportation of people living with HIV from the United Kingdom until antiretroviral treatment becomes more widely available. The AHPN is also asking MPs to support the campaign by endorsing Early Day Motion 1556.

Background information

• There are 40 million people living with HIV world wide and only 1.3 million receiving treatment.
  www.unaids.org
• There are 63,500 people living with HIV in the UK, of which 21,500 are African born. There were 7450 new infections in 2005.
  www.hpa.org.uk

EDM 1556 This house notes that there is a clear contradiction between the UK’s policy aim of universal access to treatment for all those who need it by 2010 and the deportation of people living with HIV who are on treatment to countries where treatment is not readily available or affordable; notes that the withdrawal of treatment increases the body’s vulnerability to opportunistic infection and will result in drastically shortened life expectancy, and welcomes the launch of the African HIV Policy Network’s campaign calling on the Government to allow HIV positive people on HIV treatment to stay in the United Kingdom, until they are able to return home when access to antiretroviral treatments becomes more widely available.

International Development Committee 18 December 2006, HIV/AIDS: Marginalised Groups and Emerging Groups stated: We see a clear contradiction between a policy of routinely charging those failed asylum seekers who want to start a course of treatment after their application has been rejected and Government advocacy of the universal access goal. We believe that undermining the needs of minority groups in this way is a denial of their human rights and weakens DFID’s international leadership on this issue. We believe that DFID should play a role in ensuring that asylum seekers living with HIV are not returned to countries where access to ARVs is not practical. We regret that more progress has not been made on these matters since our last report.

The Joint Committee on Human Rights Tenth Report of Session 2006-07 report “The Treatment of Asylum Seekers” stated: We accept that there is no universal worldwide access to free medical treatment, but recommend that on the basis of common humanity, and in support of its wider international goal of halting the spread of HIV/AIDS, the Government should provide free HIV/AIDS treatment for refused asylum seekers for as long as they remain in the UK. Absence of treatment for serious infectious diseases raises wider public health risks. The Government should not deport a person in circumstances where that person is in the final stages of a terminal illness and would not have access to medical care to prevent acute suffering while he is dying.

See also:

www.keele.ac.uk/research/lpj/Law_HIV-AIDSProject/MarchPresentations/HermioneMcEwen.ppt 42 KB

Summary of EACS studies

Good overview session on resistance – key slides on importance of <50 copies/ml, especially Kaplan-Meier graph – ie that need long term data to see clinical impact of difference of additional resistance to one family – resistance is just as important now as ever – we are talking about lifelong treatment, and are unlikely to see another block of new drugs for years. Good models for how resistance develops etc.

1. Earlier treatment and overview lectures. As with IAS reports including potential protective effect of treatment against cardiovascular disease. More solid confirmation that guidelines will change to earlier treatment. Lots of potential advantages including the UK CHIC CD4 study showing the lower your CD4 count when you start, the lower it will remain.

2. European guidelines – important because they are being more widely produced and distributed. Potential to normalise (and improve) average care across Europe, in the same way that national guidelines for example in the UK) have improved care. Included management of treatment and complications (lipids, coinfection etc). Larger picture – shown in other presentations – is what to do when guidelines are not followed, either because of late diagnosis, variable medical care, or patient choice?

3. Tesamorelin – growth hormone releasing factor. First, reduces central fat by 20% by 24 weeks, especially in patients with higher VAT, but reaches (dose-related?) plateau that is maintained to week 52. Stopping GRF reverses effect. Use with switch strategy? Much more tolerable that rHGH. Impact on other aspects of fat accumulation (shoulders, breasts) is unclear.

4. PK studies – range of interesting, generally small studies, including late breaker – on drug levels with late dosing:

• ATV/r vs LPV/r once and twice daily. Loss of RTV at 12 hr with LPV/r BD means levels drop, and once-daily 30-40% already below minimum target. ATZ/r more forgiving in all patients if late by a few hours. Wide variability though for all.
• several NVP once-daily studies – generally supporting switch, but not as initial treatment
• atazanavir twice daily study, when unboosted (study suggesting target concentration should be 300ng7mL rather than 150 ‘probably’ not correct).
• dose adjustments for NVP or EFV using TDM showing wide range of options

5. Two comparative randomised studies in treatment naive pateints:

• ARTEMIS – darunavir/r QD vs Kaletra in naive patients (n=267 BD 57 QD), ARTEMIS. DRV showed greater % pts suppressed at 48wks, especially if baseline viral load >100,000. Kaletra QD vs BD not randomised though. Reduced ritonavir vs twice dailly darunavir/r. New trials in experienced patients, switch once suppressed option?
• GEMINI – saquinavir/r vs Kaletra in naive patients. 48 week results showed saquinavir/r was on-inferior, with generally similar outcomes, with less of an increase in triglycerides in favour of saquinavir.

6. HIV and ageing is raised several times, including a poster talking about difficulty of normalising CD4 counts when you start treatment over 50 years of age.

7. UK CHIC switch study – significant percentage of people don’t switch following guidelines, and some don’t switch at all, even with viral load over 50 copies/mL for over a year. Analysis of time impact doesn’t explain this. Really need link to clinical results from the delayed switch.

8. Costs – raised in lots of studies – several pointing out the treatment interruptions save money. One point from the earlier treatment discussion that isn’t supported in several models, is that earlier treatment will have no long term impact on cost. The actual year or two disappears very quickly, and given current situation of 60% starting with a CD4 count under 200, may actually save costs on inpatient and complication costs.

9. DRV/r vs TPV/r – lots of resistance analyses and studies – but is there an easy answer to when each one is more effective – lots from TPV, but when do advantages of better virological response outweigh concern with liver toxicity and higher ritonavir boosting dose. When doesTPV/r have an advantage? (one for Mark….)

10. Chelsea and Westminster raltegravir expanded access programme results. Good report of how new drugs should be used, and why expert management of drug resistant patients is a specialist area. Very small numbers but one to follow.

11. Lopinavir/r monotherapy studies – lots of them, with longer follow-up results. Problem of low level blips (ie people who blip with viral load to 50-500 rather than maintained <50 copies/mL. , and cant see why not use tolerable nukes, or even nevirapine. Interesting part of MONARK presentation suggested that this may be less effective in non-B compared to sub-type B infections. This seemed to be explained by other factors including adherence. Non-B actually had strong early response to week 16. Nothing clarified by the study. Raised issue of how ‘adherence’ is measured in range of studies – also unsatisfying that nothing is standardised.

12. HAART may normalise some levels of antioxidants (compared to that of HIV-negative control group). PK study form Liverpool. Questions – need for third measure, variability in the control group, etc – not my area but would be nice if the methodology is rigourous, and will please some people if it is confirmed.

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