Therapy Interruptions: In Chronic HIV

Therapy Interruptions When Viral Load is Detectable in Highly Treatment Experienced: update on German Research (V Miller). Veronica Miller and her German research colleagues reported at the 1999 Salvage Therapy Workshop on the concept of treatment interruptions for individuals with treatment experience and resistance and detectable HIV viral load. Miller's study is a retrospective analysis of patients who took a treatment interruption for whatever reason. They were not treated with an interruption as part of a strategy. Miller and colleagues previously reported observing that for treatment experienced patients for whom resistance to HIV drugs was detectable and after a lengthy interruption, resistance could become undetectable in the blood for a good proportion of patients in their analysis. Their data suggested that patients would respond better after restarting therapy following the interruption, than if they switched their regimen without a therapy interruption. Miller's recent report dashed hopes. At the 2000 Salvage Workshop in March, Miller's abstract reports that of 195 treatment interruptions, 169 were first treatment interruptions, 20 second, 4 third, and 2 fourth. 49 were extensively PI pre-treated, 14 were less extensively PI-experienced, and 106 patients were minimally PI experienced. There was evidence of a shift from resistant to sensitive in all three treatment groups in 35/55 (64%) of patients, and this was distributed in all 3 treatment groups regardless of how much PI experience they had. Miller reported that although there may be an initial virologic response, there is a high rate of virologic rebound in this cohort of patients (73% in the original cohort of 33 patients, and 86% rebounded in the expanded patient group numbering 163). Miller's average reported time to recover CD4 declines experienced during interruption raises concerns.

At Retrovirus, Steve Deeks reported on his study of 18 patients with virologiuc failure (>2500 copies/ml) who were randomized to discontinue therapy, and that the median CD4 drop was 94 cells (range -28 to -126), and the median increase in VL was +0.82 log (range -0.34 to -.92 log). Their baseline CD4s averaged 245 and viral load 4.6 log (about 40,000 copies/ml). He also reported that NRTI resistance persisted often at much reduced levels, after reversion to a fully PI susceptible virus in 7 patients. Deeks also reported at Retrovirus that although resistance was undetected in plasma following interruption, resistant virus identical to baseline was cultured from PBMCs 12 to 36 weeks after therapy discontinuation in 4 of 8 patients showing phenotypic reversion. Additionally, at the Resistance Workshop, Alan Hance (see more details in article earlier in this newsletter) reported that although resistance was undetectable in some individuals undergoing STIs using conventional genotyping, resistance could be detected using an ultra-sensitive PCR technique.

On the other hand, patients are interrupting their therapyóor, as often, taking "drug holidays"-- because they want a break from the side effects and toxicities. They also feel they need a break from the difficult demands of maintaining adherence to the daily routine of taking complicated drug regimens. If a person's CD4s are relatively high when they start an STI and their viral load is 1000 copies/ml or undetectable, the risks in interrupting therapy may be less. It's been estimated that CD4s can decline 30% after stopping therapy, so a rule of thumb could require 450 CD4s. But I think Miller's and Deek's data on CD4 decline, and Miller's data on CD4 recovery reported below, suggest that there is a clear risk for the person with relatively low CD4s and higher viral load.

Results: CD4s, Viral Load & Clinical Events

STIs in Chronic Infection When Viral Load is <50 copies/ml

Two studies are reported on below, both showing different results. But there were some differences in study design worth noting. The Swiss-Spanish study was reported at Durban, showed negative results from conducting multiple interruptions, and was the largest STI study to date. The therapy interruptions in this study consist of 2 weeks in length followed by 2 months back on therapy. The second study below was reported at the Resistance Workshop in June. It was much smaller (n=10) and the interruption cycles were different: interruptions tended to be longer, and time back on therapy was longer. Do these differences in the amount of time off and on therapy make a difference?

Swiss-Spanish STI Study. The report came from Dr. Bernard Hirschel at Durban. And is called The Swiss-Spanish Intermittent Trial, or SSITT. 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. Patients 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. A major purpose behind sequential interruptions is to prime the immune system to control HIV.

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. Hirschel stated that if 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.

Spanish STI Study in 10 Treatment NaÔve. However, this small 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 protease 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. Felipe 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.

Commentary by 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?órandomized, well-controlled studies are indicated. NNRTI Effect. 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 non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens.

Commentary by Michael 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 lessen 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 .