STIís in Chronic Infection

Durban Report by Mike Norton, PA, Greenwich House, NYC; Resistance Workshop Report by Jules Levin

Certainly the most scientific curiosity was the presentations surrounding structured therapy interruption.  This has been a topic in HIV medicine that has been receiving much attention over the past year.

NIH Studies. Anthony Fauci, MD from the NIH gave a presentation on Tuesday during his plenary talk giving a rationale for STIís.  To recap, he stated that due to the fact that early in the course of HIV infection certain cells are infected that last years if not decades.  These cells remain a barrier to full body eradication of HIV because they are difficult to purge during there often long inactive periods.  Also because our currently available antivirals are unable to fully penetrate all areas and stop all active replication the long lived reservoirs of cells are probably reseeded constantly again making eradication with the currently available agents probably impossible.  He reminded the audience of his and others work in this area of attempting to eradicate HIV and their lack of success.  He spoke of the phenomena where HIV specific CD8+ T-cells diminish over time when a personsí viral load is undetectable for long periods of time.  He proposed that by interrupting HAART a person may prime these HIV specific cd8+ís and that may in turn lead to prolonged intervals before viral rebound after subsequent HAART interruptions.  He did however caution that individuals who had progressed with HIV infection prior to starting HAART would probably not be able to be off therapy for extended periods of time.  He stated to the audience that he felt it was reasonable to pursue this research, but that it was in its infancy and that like the thought of eradication a few years ago may not prove successful at this time.

Two presentations were late breakers from the Fauci group at the NIH.  Mark Dybul, MD is leading this work.  Dr. Dybul first set the stage by stating the goal of being able to reduce the total amount of antivirals patients might have to take in a year, month, or even week.  Dr. Dybal asked the rhetorical question of whether less drug could end up with at least the same immunologic results and perhaps even less side effects.  He presented data on three studies each taking varying approaches to interruptions: one was 2 months on and 1 month off therapy; a second approach was 7 days on and 7 days off therapy; and the third was 2 days on and 5 days off therapy. Participants in the studies had viral load suppressed to <50 copies/ml. This is important because stopping meds with detectable viral load could potentially risk increasing the development of resistance to the drugs one was taking. To this end he presented abstract #LbOr11.  This study is just underway and he reported some very early results on a very few patients.  This study is scheduled to enroll 70 patients.  35 are to be the control arm and continue receiving their traditional continuous HAART.  35 are to receive intermittent HAART, defined as 1 month off therapy then 2 months on.  The end points are 1 and 2 years, with the question at that time point being do the patients who took HAART intermittently have the same viral loads, T-cells, and adverse events as those who did not interrupt their HAART?  9 patients in the intermittent HAART arm had gone through 2 cycles.  4 of the 9 pts during their second interruption of HAART had a lower amount of viremia that returned when compared to the first interruption of therapy.  1 pt. had a higher amount of viremia on the second interruption and 4 pts. showed no change in the amount of viremia that returned on the second interruption when compared to the first.  All patients returned to below the level of detection (<50 copies/ml) after their first interruption but prior to starting their second. While there was some drop in CD4 count after the first interruption, there was less of a drop after the second interruption.

In his second presentation, Dr. Dybul reported on what he termed ìshort cycle interruptions.î  Abstract #LbOr12.  In this pilot study there were 10 pts. 5 in each arm.  One arm is 7 days on therapy and then 7 days off.  The second arm was 5 days off therapy and 2 days per week on.  All patients who entered were on D4T, 3TC, Indinavir, and Ritonavir.  Failure in this study was decided at the end of the periods when a patient was taking drug and was defined as a viral load of >500 copies/ml on 2 consecutive occasions.  The conclusions after 14 weeks was that the 7 days on and 7 days off maintains suppression and there was no CD4 loss, and that the 2 days on 5 days off in a week doesnít. There was difficulty in quickly reestablishing viral control when going back on therapy with the 2 days on & 5 days off therapy approach: 2/3 patients had about 1000 copies/ml viral load but were able to achieve <50 copies/ml after restarting therapy. The 2 days on 5 days off part of the study has been terminated and the 7 days on, 7 days off will continue and be expanded.

What's the theory behind such brief times on and off therapy? These brief pauses are done for short periods of time to prevent damage done to the immune system (including, I think, CD4 declines) when medications are stopped and viral load rebounds exposure to HIV. It's suggested that viral load may take one to two weeks to return so it's hoped that during only one week off therapy virus will not grow back enough to do damage.

Its strongly recommended not to experiment with these approaches to interruptions outside of research settings because there is unresolved concern that drug resistance could develop and endanger long term use and success with antiretrovirals.

Patients like some semblance of continuity and going off and on therapy (7days on- 7 days off) so often can be very chaotic and disruptive. I question whether a person can get used to such a regimen.

Commentary: Dybul and Fauci were harshly criticized for presenting their data too preliminarily (14 weeks!). Many expressed concern that releasing preliminary data like this encourages patients to experiment

with unproven treatment approaches and may put individuals at risk (Jules Levin).

Swiss-Spanish STI Study. The final report came from Dr. Bernard Hirschel.  The study is called The Swiss-Spanish Intermittent Trial or SSITT, abstract # ThOrB747.  This is the largest STI study to date.  It is still ongoing, therefore these are interim 1-year results.  There are 122 chronically HIV infected patients in this study. Viral load on entry had to be <50 copies/ml.  The median time patients had been on HAART prior to entering the study was 25 months and the median time below the level of detection was 21 months. Most patients were ART-naÔve before HAART, without treatment failure, and had never taken NNRTI. They were on a PI containing regimen for this study. Pts. had to have >300 cd4+ T-cells.  Median cd4+ T-cells were 718 on entry.  This study consists of 4 cycles of therapy interruption.  Each interruption is 2 weeks in length followed by 2 months of therapy.  There was little evidence of a consistent trend towards viral control using this interruption-cycling approach. The study results also suggest risks as viral loads increased appreciably during interruptions for some individuals;15% of patients were unable to reestablish their viral loads to <50 copies/ml after the 8-week retreatment; between 2.5% to 7.5% were unable to reestablish viral load to <50 copies/ml after each two week interruption. For most participants there was no trend of decreasing viral loads following multiple interruptions, but for 20% there appeared to be decreasing viremia with each interruption.  

After 40 weeks all patients are to stop therapy and not re-start until their viral load exceeds 5,000 copies/ml.   After the first interruption, with 120 patients taking that 2 week break in therapy, the median viral load rebound was 2.8 log copies/ml with a range from less than 1 log to 6 log copies/ml.  24% of those patients saw no rebound in HIV to >50 copies/ml during this first interruption.  12.5% had a viral load rebound to >100,000 copies/ml.  56 patients have already experienced 4 STIís.  Looking at those patients who have had 4 cycles, Dr. Hirschel reports that they have noticed no trend of decreasing viral loads with each successive interruption.  14% saw no rebounds in viral loads during the 2 week breaks.  28% saw the virus come back at the same level with each STI.  27% saw an increasing amount of HIV viremia with each successive STI.  20% did see a decreasing amount of viremia with each STI.  And in the remaining 10% there was no discernable pattern.  19 patients had to discontinue their participation in the study at some point due to not reaching <50 copies prior to the time they were scheduled to begin their next interruption.  Fortunately, most of those were between 50 and 200 copies/ml.  Only one patient had evidence of resistance.  13 patients reached the endpoint of the study and according to design discontinued HAART altogether.  11 of those 13 subsequently re-started HAART due to their HIV rebounding to >5,000 copies/ml.  2 patients experienced acute antiretroviral syndrome.  Dr. Hirshel stated, ìif he had the chance to re-design the study he would expand the time on drug to 12 weeks from 8 due to the discovery in this study that a number of patients require a full 12 weeks to re-suppress HIV after a 2 week interruption of HAART.

Commentary:  This study has been the largest to date on STIs. One could say that if this study were designed differently, such as varied times on and off drug, results may have been different. If one were to remain back on drugs for longer than 8 weeks, you could speculate that would help viral control and possibly prevent inability to reestablish viral load to <50 copies/ml. You could also suggest that additional interruptions could lead to better responses--better control of HIV. Nonetheless, there was considerable talk in Durban that these study results seriously undermined the potential benefit of STIs for individuals with chronic HIV.

Spanish STI Study in 10 Treatment NaÔve: a different result

A Spanish study presented at the Resistance Workshop (details on NATAP web site in Conference Reports) suggested differently.

Ten antiretroviral naÔve patients with chronic HIV-1were recruited from the Spanish EARTH-1 Study . Their baseline CD4 was >500, and VL was >10,000 copies/ml (range 14,700-504,000). They were treated with d4T, 3TC, and ritonavir or indinavir for 52 weeks.  After one year of HAART all had a plasma VL <20 copies/ml. Prior to STI patients had <20 copies/ml in plasma for >32 weeks. In this small study in chronic infection 4/8 individuals were reported to have spontaneous viral load reductions after several therapy interruptions.

At baseline, VL was required to be <20 c/ml and therapy interruption was for 4 weeks or until VL increased to >200 c/ml. Everyone was reintroduced to therapy for 6 months. At week 28 a second therapy interruption was started if VL was <20 c/ml. Therapy was reintroduced 1 month after VL >200 c/ml if VL did not drop spontaneously. Therapy was reintroduced and maintained for 6 months and a third interruption was introduced if VL was <20 c/ml for a third and last time. This time therapy was only reintroduced when VL was about 10,000 c/ml or greater. At weeks 0, 28, and 96 (first, second, and third stop, respectively), plasma VL was <20 c/ml in all cases and below 5 c/ml in 7 of 10 cases (first stop), and in 7 of 9 cases after the second stop and third stop (one patient was lost to follow-up). A rebound in VL was detected in all cases with a mean (SE) doubling time (DT) of 2.23 (0.32) in the first stop, 3.38 (1) days in the second stop and 3.25 (0.38) in the third stop (p=0.05, for the comparison between DT in first versus third stop). In two patients, DT increased from 2.48 to 8.66 and from 3.85 to 8.66 days, respectively.

At the second stop, in 4 of the 9 patients, VL rebounded to similar levels as baseline (week -52) and dropped spontaneously thereafter (0.8, 0.8, 1.3, and 2.09 log copies/ml, respectively). These 4 patients developed strong and broad HIV-1 specific CTL responses and a strong CD4 lymphocyte proliferative response to HIV-1 antigens.

After the third stop, a rebound in plasma viral load was detected in all cases. Six of the 8 patients had a VL set-point significantly lower than baseline (from 0.5 to 1.7 log). And, 4 of 8 patients had VL < 10,000 c/ml (range 650 to 9,000) after 8 months off therapy. Recovering of specific CTL and CD4 lymphocyte response was detected in 5 of the 8 patients. After the first, second and third stops, genotypic or phenotypic resistance to reverse transcriptase or pritease inhibitors was not detected.

HIV- Specific Immune Responses at Stop 3

At baseline while on HAART, none of the 8 patients had a CD4+ proliferative response against HIV-1 p24 antigen, nor did they have a CTL HIV-1 specific response. During the third interruption, 6 of 8 had a CD4+ proliferative response against HIV-1 p24 antigen and 5 of 8 had a CTL HIV-1 specific response. Garcia reported that HIV-1 specific immune response (both CTL and CD4 responses) correlates with spontaneous control of viremia after stops 2 and 3.

Garcia described two examples of patients in the study--one who responded to the STI and the other who did not. Subject #2 had a baseline VL of 27, 300 c/ml. After the first interruption VL increased to 3000 c/ml. After the second interruption VL rebounded to similar level as baseline VL but VL dropped spontaneously to 200 c/ml. Therapy was reintroduced, and after the third stop VL increased to 6000 c/ml, but spontaneously dropped to 500 c/ml and has maintained this for 8 months. In subject #12, STI was not successful. At baseline on HAART VL was about 27,000 c/ml. After the first interruption VL rebounded to 300,000 c/ml, but went to undetectable after therapy was reintroduced. After the second stop VL increased to 70,000 c/ml and again was reduced to undetectable after therapy was reintroduced. After the third interruption VL rebounded to 40,000 c/ml and remained between 10,000 and 40,000 during the 8 months of follow-up without antiretroviral therapy.

Safety

After the first, second and third stops, genotypic and phenotypic resistance to reverse transcriptase or protease inhibitors were not detected. A quick virological response was observed after reintroduction of the same antiretroviral treatment after the first and second stops, and in the two patients who restarted ART after the third stop. CD4 T lymphocytes dropped significantly after the first, second and third stops to a level similar to the level before starting ART.

Commentaryby Jules Levin

This study was conducted in a unique population of individuals, who were in relatively early disease with relatively high CD4s and who had VL <20 copies/ml for 12 months. At Sitges, a  good deal of discussion questioned the vailidty of these findings. It was mentioned that there is data from a cohort in which individuals had spontaneous viral load reductions while not on therapy. I think that in order to put this controversy to rest--do STIs induce viral control in a certain population--, randomized well-controlled studies are indicated.

Another important consideration is that because efavirenz (45 hours) and nevirapine (24 hours) have long half-lives (remain in blood for days at decreasing levels after stopping the drugs), treatment interruptions may be risky for developing NNRTI resistance for individuals taking nonnucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens

Commentary by Mike Norton

Understandably doctors and patients would like to lessen the amount of drugs patients must take and still preserve their immune systems from HIVís destruction.  Everyone involved in HIV medicine would like to lesson the side effects and body changes that too many experience while taking HIV antivirals.  Still I am concerned that while the scientific community is attempting to answer legitimate questions surrounding the possible role of STIís, patients will decide without the evidence, that taking breaks from HAART is safe.  This has not been determined and the risks are currently significant:  development of drug resistance, slippage in immunological gains during HAART, inability to re-suppress HIV after interruption, and a risk of acute re-seroconversion reaction if the virus comes back vigorously during a therapy interruption.  My advice to patients who are tolerating antivirals fairly well is to wait at least 6-12 more months until further information on these studies are completed before embarking on the STI path.