Treatment interruptions, structured and unplanned, immunotherapy and what’s in store
Dr Mike Youle, MB, ChB for HIV i-Base
So here goes the pendulum again, this time against drug [read antiretroviral combination] treatment.
Several studies were presented at this conference that argued for later time of starting treatment with HAART as no clear clinical advantage could be determined in those who started treatment with T4 cell count levels above 200 cells/mm3. This was also since the balance between benefit (avoidance of HIV-related opportunistic infections and tumours) and drug associated toxicity appears to be swinging to the latter. Lipodystrophy, increased cardiac risk, facial wasting, have all become common words linking together a general physical, symptomatic and psychosocial constellation of problems at least in some part due to treatment (iatrogenic).
I suppose the most important issue to come out of the conference on treatment interruptions is that they are not all alike. The information on structured (i.e. planned and repetitive) interruptions is much stronger for primary or early infection than for chronic or late-stage disease. This is logical in the regard that HIV specific T4 helper responses are still relatively preserved and thus the host immune function retains more ability to suppress HIV. Bruce Walker summed up the oral session on this subject with a presentation on the ongoing work he and Eric Rosenberg have presented before. Fourteen subject at primary HIV infection [PHI} with a very high median viral load of 10million copies/mL had treatment interrupted when they achieved <50 copies/mL and then restarted if the HIVRNA rises above 5,000 copies/mL.
To date 6 subjects have not failed by these criteria whereas 8 subjects restarted and re-suppressed and after a second interruption only one subject failed to stay low initially. At a later time-point several have either started treatment or rebounded. These data are very preliminary and of course only apply to the very difficult to identify group of PHI patients. However it is tantalising to believe that this would suggest that in some initially infected subjects control of HIV is achievable by a combination of treatment for a period of time followed by exposure to HIV again. Several studies are examining the utility of using HIV vaccines to expose PHI HAART treated patients to HIV genetic material without using HIV itself.
Marty Markowitz, from David Ho’s group, presented data on other PHI treated subjects who then had STI’s . These subjects were seen a little later in the course of their infection (median 65 days after infection) than those presented by Walker. What became clear is that the responses were also less impressive with only 3 subjects out of 5 studied controlling HIV after STI, 5 had levels between 5000 and 20,000 copies/mL and 7 restarted treatment. So it would appear that even a short delay in treatment might have negative implications for the outcome of this strategy.
When it comes to those who have had longer periods of treatment with HAART and in who therapy was started well after seroconversion the results of STI studies are less than earth shattering. The largest study to report to date and what looks like the one which will define the lack of benefit of this approach is the Swiss-Spanish Intermittent Treatment Trial . Each new conference brings less hopeful noises form this group and it seems that when it finally gets to peer review the outcome is likely to show an heterogeneous response to STI in this population. Currently there are 132 subjects entered (less than 50 copies/mL for over 6 months) of that 99 have been followed through 52 weeks. Subjects had 4 cycles of 2 weeks off 8 weeks on therapy and then stop until HIV RNA rose to 5,000 copies/mL. Currently 21% have achieved the aim of not having to restart at this time-point. Although not data yet is available concerning the HIV specific cellular immune responses at last eye-balling the data this does not seem to be a fantastic strategy.
For those subjects however who are losing control of their virus and whom are at later stage of disease there may be more logic to stopping therapy for a while. The balance lies between allowing the viral swarm to settle down to a more sensitive mix of strains for the next therapeutic opportunities arise. Steve Deeks presented more data from his cohort of failing subjects in whom he has well characterised resistance patterns and also fitness of virus swarm after ceasing therapy . He showed that in 19 subjects with detectable virus undergoing an STI of median duration of 18 weeks that the median T4 drop was 95 cells/mm3 and a viral load increase of 0.74 log10copies/mL. 18 subjects showed a reversion to wild type of protease inhibitor sensitivity. During follow-up on salvage regimen 47% achieved a viral load <50 copies/mL and failure to suppress resulted from persistence of resistance and re-emergence of virus related to prior therapy
So what did the 8th Conference on Retroviruses and Opportunistic Infections have on offer as immunotherapy.
Well there was a little further information on therapeutic vaccines . Jin and colleagues from Rockefeller University in New York enrolled 4 subjects to receive HAART after PHI as well as four vaccinations with a combination of two vaccines HIV-gp160 and the canary pox vector vCP452 expressing HIV gag ,pol env and nef , the new vaccine form Aventis-Pasteur. No adverse events occurred and the vaccinees developed increased antibody responses to envelope proteins and to p24 antigen. In addition 6/14 mounted a temporary HIV specific T-helper response. A disappointing response perhaps but maybe an indication that with better antigens and improved adjuvants then this approach may yield some benefits.
Hecht and co-workers from the University of San Francisco presented some information on the utility of combining interleukin-2 (IL-2) with HAART in PHI . Subjects received Combivir and nelfinavir, with or without up to 6 cycles of IL-2 7.5MIU twice daily for 5 days. To date 28 subjects (3 IL-2) have been followed for greater than 24 weeks. Apart from a weak trend to better viral suppression in the IL-2 treated group there did not appear to be benefits from this intervention in the short-term.
IL-2, however did seem to be beneficial for those subjects who received it in ACTG328 presented by Ron Mitsuyasu . In this large multi-centre US study in subjects starting HAART with T4 counts between 50 and 350. At week 12 if less than 5000 copies/mL subjects were randomised to HAART alone (N=52) or HAART plus continuous IL-2 (CIV) 9MIU OD for 5 days every 8 weeks (N=54) or HAART plus subcutaneous IL-2 (SC) 7.5MIU BD for the same cycle duration and frequency. After 6 cycles and an improvement in T4 count >100 and >25% subjects could switch to SC form CIV IL-2. Results are shown in the table below.
|Median CD4||HAART||HAART plus CIV IL-2||HAART plus SC IL-2|
|% with >50% rise week 12-84||41||86*||77*|
*p<0.001 vs HAART alone
Clearly there is a significant T4 advantage to this intervention and the ESPRIT and SILCAAT studies are now ongoing in order to determine if these T4 cells protect as effectively as those produced by HAART. Interestingly the rise in the SC group over 60 weeks was similar to that seen in the UK IL-2 Vanguard study which did not require the subjects to take antiretroviral agents.  Currently the TILT study is recruiting at the Royal Free, UCH and Brighton Hospitals to ascertain if patients could switch from Antiretrovirals to Interleukin-2 as an alternative treatment. .
Further supportive evidence for the role of IL-2 in HIV management came from a long term follow-up analysis of subjects from the US National Institutes of Health who have received IL-2 for greater than 3 years . In this group what is clear is that of the 746 cycles of IL-2 administered to 77 subjects the ratio of cycles/subject decrease from 3.5:1 at 6 months to 0.1:1 at 84 months. Mean interval at that time was 26 (range 2-60 months). This suggests that at least in those who receive antiretrovirals in conjunction with IL2 the cycle rate can be sustained at a low level. Functional immunity also seems to improve over time in subjects on IL-2. Durier and colleagues examined 65 subjects from the French ANRS protocol where they received stavudine (d4T) plus lamivudine (3TC) plus indinavir with or without cycles of IL-2 at 7.5MIU BD for 5 days . After Week 56 median increase in T4 cells was 886 (118-2,487) in the IL-2 group compared to 232 (-30-1,204) in the control group. Increases in CD45RACD62L (naive T4 cells) was greater in the IL-2 group (475 compared to 83; p<0.001). The proliferative responses to candida and tetanus improved to a greater degree in the IL-2 treated patients (p<0.001).
All these data point to interleukin-2 being the most likely first licensed candidate for HIV immunotherapy. There are many trials ongoing and the toxicity profile although unpleasant during a cycle is neither dangerous nor prolonged. In addition these and other studies appear to show if anything that the treatment becomes more rather than less effective over time. Other cytokines such as IL-12 may be beneficial in HIV disease and are also currently under study.
- Markowitz M, Jin X, Ramratnam B et al. Prolonged HAART Initiated within 120 Days of Primary HIV-1 Infection Does Not Result in Sustained Control of HIV-1 after Cessation of Therapy. 8th CROI. Abstract 288
- Fagard C, Lebraz M, Gunthard H et al. SSITT: A Prospective Trial of Strategic Treatment Interruptions in 128 Patients. 8th CROI. Abstract 357
- Deeks S, Wrin T, Hoh R et al. Response to Salvage Therapy in Patients Undergoing a Structured Treatment Interruption. 8th CROI. Abstract 292
- Jin X, Ramanathan Jr. M, Barsoum S et al. Safety and Immunogenicity Study of vCP1452/rgp160 Therapeutic Vaccines in Patients Treated with HAART for Over Two Years. 8th CROI. Abstract 21
- Hecht FM, Levy JA, Martinez-Marino B et al. A Randomised Trial of Interleukin-2 (IL-2) Added to HAART for Primary HIV. 8th CROI. Abstract 407
- Mitsuyasu R, Pollard R, Gelman R et al. Prospective, Randomised, Controlled Phase II Study of Highly Active Antiretroviral Therapy (HAART) with Continuous IV (CIV) or Subcutaneous (SC) Interleukin-2 (IL-2) in HIV-Infected Patients with CD4+Counts of 50Ñ350 cells/mm3: ACTG 328-Final Results at 84 Weeks. 8th CROI. Abstract 17
- Youle M, Fisher M, Nelson M et al. Randomised study of intermittent subcutaneous interleukin-2 (IL-2) therapy without antiretrovirals versus no treatment (UK IL-2 Vanguard to the Esprit Study). 13th World AIDS Conference, Durban 2000. 8th CROI. Abstract LBOr28.
- Chaitt D, Metcalf J, Kovacs J et al. Extended Therapy with Subcutaneous Interleukin-2 (scIL-2) in HIV-Infection: Long- Term Follow-Up of 3 Trials. 8th CROI. Abstract 347
- Durier C, Emilie D, Estaquier J et al. Effects of Subcutaneous (SC) IL-2 Combined with HAART on Immunological Restoration in HIV-Infected Patients. 8th CROI. Abstract 345