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Treatment Interruptions, STIs
Written by David Margolis, MD, University of Texas, Southwsetern Medical Center
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Treatment Interruptions: cycles, pauses, are just plain stopping?
Interruption of antiretroviral therapy occurs every day as part of clinical practice, and as part of everyday life living for many with HIV infection. Over the past several years prescribed interruptions of therapy have been proposed to accomplish a variety of goals: to improve the immune response via auto-vaccination with HIV, to diminish the proportion of circulating drug-resistant HIV and improve the response to salvage therapy, or to reduce the exposure to antiretrovirals and ameliorate drug-related toxicities.
A great deal of data was presented at the 10th CROI around this issue, and well summarized by Guenthard for those with the stamina to stay and listen to the meeting's final symposium. Little support was found for an auto-vaccination effect of STI, as cytotoxic T cell responses (CTL) returned upon interruption, but without the appearance of a new, broader, or more potent response. Further several studies showed that viral load rebounds were not significantly different after STIs, suggesting a lack of improved immune control. In the special case of HAART given upon acute HIV infection or shortly thereafter, several small studies of cycled or prolonged interruption (posters 512, 513, 517, 519) came to differing conclusions as to the benefit of therapy in acute infection and its interruption. These differences may reflect small or disparate samples.
There are many potential drawbacks to treatment interruptions. Resistance, particularly to drug with low genetic barriers (M184V resistance for 3TC, and K103N resistance for efavirenz) has developed during STIs. CD4 declines, relapse of an acute retroviral syndrome, and opportunistic infections have all been reported during STIs. On the other hand, some patients have remained stable following long interruptions. There is clearly short-term amelioration of some drug-related toxicities following treatment interruption, long-term cumulative benefits of cycling interruptions have not yet been demonstrated. Clearly the devil is in the details as to when therapy is interrupted, and how.
A pilot study (Abstr. 64) of intermittent therapy following the one week on/one week off model initially piloted by the NIAID Clinical Center group. It was performed in Thailand in a group of patients with a history of dual NRTI therapy followed by treatment with two NRTIs and a PI in several clinical studies. Three cohorts of such patients, approximately 25 patient per group, were then randomized to continued HAART, therapy interruption until CD4 counts dropped below 350/ul, or one week on/one week off intermittent therapy. At entry CD4 counts were in the 500-700/_m range; 75% of the subjects were men. At 48 weeks of study, 13% of the subjects in the CD4-guided interruption arm had suffered CD4 declines to < 350 cells/ul, but all but one patient in the other arms had CD4 counts > 350 cells/ul. However, in the week on/off arm 7 patients had virological failure, one had CD4 < 350/ul, and 2 were lost to follow-up. Only 35% of patients in the on/off arm had HIV RNA < 50 copies/ml, while 96% of the subjects in the continuous arm were < 50 copies/ml. Of 9 patients from whom genotypes were available in the on/off arm, 4 had resistance mutations (3 in RT and 1 in PR). The Swiss Cohort (poster 639) also found evidence of significant viral replication within one week of an interruption.
Overall the one week-on-one-week-off strategy appeared to be an unmitigated disaster. No evidence of decreased toxicity or improved immune control was reported, at the cost of a striking incidence of virological failure and the appearance of resistance when compared to continuous therapy. The CD4-guided arm appeared to have done well, but the median CD4 count at reinitiation of therapy was 536 cells/ul, suggesting that therapy was re-initiated after small declines in CD4.
Further support for the use of prolonged interruptions without cycling to spare toxicity or cost was provided by a preliminary report of CD4-guided therapy from the Barcelona group (Abstr. 65). Of 120 patients with a median CD4 count of 800/ul and HIV RNA < 50 copies/ml for a median of 40 months, half were randomized to interrupt therapy. Therapy was restarted if HIV RNA > 100,000 copies/ml or CD4 count dropped < 350/ul. 44% of subjects stayed off therapy for 48 weeks, and almost all of the 56% who restarted did so because of viral rebound > 100,000/ml at a median of 8 weeks after stopping. Those who restarted also had a steeper CD4 decline slope and a lower nadir CD4 cell count. 33 CD4 cells/month were lost in those who remained off therapy for 48 weeks.
Stephano Vella reported on 56 week results of longer cycled interruptions from an Italian cohort (Abstr. 66). 137 patients continued therapy, while 136 underwent 1 month on/3 months off cycles. Two-thirds of subjects used NNRTI-based HAART; median CD4 at entry was 691 cells/ul. Due to the long half life of NNRTIs, in those on NNRTIs the NNRTI was stopped several days before the NRTIs to reduce the chance of NNRTI resistance. While patients on cycled therapy generally suppressed to < 400 copies/ml on reinitiation, a disturbing trend towards increased resistance mutations, particularly NNRTI mutations, in patients undergoing cycling gives pause. No metabolic data was yet available, and given that there is therefore no data to show benefit of this strategy, such cycling should be left to the clinical investigator for now.
Conflicting evidence was presented with regard to the benefit of interruptions in the setting of salvage therapy. A large and careful study, CPCRA 064 (Abstr. 67), studied patients failing therapy with long drug experience and multidrug resistance. Salvage therapy was guided by genotypic and phenotypic resistance tests done at study entry, and patients randomized to immediate salvage or salvage therapy after a 4 month interruption. This population with advanced disease had a mean CD4 count of 180/_l, 26% had CD4 counts below 50, a mean baseline viral load of 100,000, and exposure to 5 NRTIs, 4.2 PIs, and 1.5 NNRTIs. 48% had 3 class drug resistance on testing. There was no difference in the number of active drugs prescribed to the two groups (2.7 vs. 2.8).
STI in this study was inferior to immediate salvage therapy. There were 22 primary endpoints (progression of disease or death) in the STI group and 12 in the no-STI group (hazard ratio = 2.57, 95% CI = 1.2, 5.5, p = 0.01). Events in the STI arm included 7 esophageal candidiasis, 4 PCP, 3 cryptosporidiosis, 2 lymphomas, and 1 CMV. Mean difference in CD4 favored the no-STI arm by 85 cells/_l (p < 0.001) for months 1-4 (STI phase), 47 cells (p < 0.001) for months 5-8, and 31 cells (p = 0.11) for months 12-20. The study closed to accrual as recommended by the DSMB based on data before full accrual.
In stark contrast, this strategy appeared to be successful in a study performed by Katalama and collaborators in France (Abstr. 68). Patients with multiple failures of therapy and very advanced HIV disease (HIV VL > 50,000cps/ml and CD4cells < 200/ml) were randomized to either immediate therapy or therapy after 8 wks of STI. Therapy consisted of 3-4 NRTI and one NNRTI ± hydroxyurea (500 mg bid) and ritonavir (400 mg bid) and amprenavir (600 mg bid) or lopinavir and a third PI (indinavir 400 mg bid or saquinavir 600 mg bid or nelfinavir 1,250 mg bid). Seventy pts were randomized, 68 started study drugs, and 63 were evaluated at weeks 12 and 24, and 64 at week 48. At baseline, median plasma HIV RNA was 5.3 log copies/ml (200,000), CD4 27/_l, duration of ARV therapy was 6.6 yrs with a median of 11 antiretroviral drugs. By ITT missing equal failure analysis, the percentage of patients with HIV VL decrease > 1 log from baseline was 26% at week 12, 24% at week 24 if immediately salvaged, versus 62% at week 12 and 50% at week 24 in the STI group (p = 0.007 and p = 0.043, respectively). Median decrease in HIV RNA from baseline was -0.37 at week 12, -0.29 at week 24, and -0.37 at week 48 in the immediate group versus -1.91, -1.08, and -0.79 in the STI group (p = 0.008 at week 12, p = 0.013 at week 24). Percentage of pts with HIV RNA < 400 cp/ml was 15% at week 12, 12% at week 24 in immediate salvage vs 38% and 32% in the STI group ( p = 0.053 and p = 0.077, respectively). Median increase in CD4 cell count from baseline was +7/_l at week 24 and week 48 in immediate salvage vs +51/ml and +69/ul in the STI group. Two subjects died in each arm. 22% and 47% of patients were still on treatment with more than 6 drugs at week 48. Three major factors were associated with virologic success: treatment interruption with reversion of resistance, adequate drug concentration, and the use of lopinavir.
It was difficult to reconcile the success of this extraordinarily intense regimen with the poor outcome of CPCRA 064. Possible explanations include the longer STI in CPCRA 064, and unique, ineffable characteristics of the French patient population. Many investigators at CROI felt that it was likely that the CPCRA experience was more likely to reflect the success of this strategy in general clinical practice.
The other side of interruptions: when to continue failing therapy and why?
Several presentations addressed the continued immunological and clinical benefits of therapy that is continued despite loss of complete (that is, for the time being, <50 copies/ml) suppression of viral replication. A synthesis of the insights into the benefits of antiretroviral therapy, the still-emerging long-term risks of therapy, and the risks and benefits of cycled or intermittent therapy is probably the most important immediately clinically applicable insight to be gained from the 10th CROI.
Steve Deeks provided complex and provocative insights during his symposium discussion of "When to Switch" (#188), and important details were available in his poster with Bob Grant and the ViroLogic group (#640). Deeks himself expressed concerns after the presentation that his studies, meant to be an experiment to explore the relative immunological benefits of different components of antiviral therapy, will be misinterpreted as a prescription for inappropriate use of HAART.
It was hypothesized that among treated patients with multi-drug resistant HIV, interruption of all drugs from a single therapeutic class ("partial treatment interruptions") might (1) maintain partial viral suppression and its associated immunologic benefit, (2) prevent overgrowth of wild-type HIV, (3) delay viral evolution, and (4) reduce drug-toxicity and drug costs. Twenty subjects were studied in this non-randomized, open-label pilot study. Subjects actually chose which drug class they would interrupt. The median baseline viral load was 3.9 log [8,000] copies/ml (IQR 3.6 - 4.5) and the median CD4 T cell count was 336 cells/ul.
15 volunteers interrupted of all PIs and continued all NRTIs; in these subjects viremia and CD4+ T cell counts were stable over 24 weeks. As expected after interruption of PIs, fasting triglycerides and non-HDL cholesterol improved. Genotypic and phenotypic resistance remained stable in all patients interrupting PI therapy through week 16-24; however, PI mutations waned and replicative capacity and viremia increased in two patients after week 24. The conclusion from this finding in this brief, small, uncontrolled study should be the insight that continued PI therapy in the presence of MDR HIV contributes to the control of viral replication, and may confer a potential clinical benefit. This is not surprising as many studies have suggested this in the past, but this experiment offers strong evidence that patients are benefiting from PIs despite resistance and viremia. The conclusion should not be that sub-optimal nucleoside therapy is acceptable in patients with MDR virus.
5 other volunteers interrupted NRTI therapy and continued PI therapy. In contrast, exhibited immediate and sustained increases in viremia (+0.03 log copies/week, P < 0.001) was observed. This is not surprising to virologists, as many studies have suggested the maintenance of RT mutations results in a virus that grows more slowly, and that this may confer a clinical benefit. Of note, three of 5 subjects interrupting NRTI therapy exhibited a delayed loss of M184V, which was temporally associated with a rise in viremia. This finding should provide satisfaction to Mark Wainberg and others, as it is the first clear and direct validation of their contention made in the 1980's that the maintenance of the 3TC resistance mutation confers a clinical benefit.
Deeks et al concluded that interrupting PI therapy in patients with multi-drug resistant HIV is associated with stable viremia, reduced toxicity, and halted accumulation of drug resistance (which may preserve future PI options). However this effect may not hold for more than 24 weeks, as illustrated in a handful of their cases. On the other hand, clinical benefits may be gained by a drug holiday of a few months. In contrast, interruption of NRTI therapy was associated with rapid rises in viremia, indicating that NRTIs may have continued antiviral effects against drug resistant HIV. Partial treatment interruptions may be appropriate for maintaining partial virologic responses in persons with limited treatment options. The critical caveat to these conclusions is the specific patient population in whom this clinical strategy might be considered. The patients in this study all had preserved CD4 counts (366/ul) and many PR and RT mutations. Such a maneuver is unlikely to work without a virus significantly impaired by MDR mutations and without a partially intact immune response. However, the findings of this group should give us pause for careful consideration in making therapy changes or interruptions, and identifies important questions to be explored in careful clinical trials.
Another important data set with regard to the decision to interrupt or
continue therapy was presented by the PLATO collaboration (146LB, session
27). This is a prospective observational study following patients from 13
cohorts in Europe, North America, and Australia. Data from 2448 patients
with 3-class drug failure was obtained, and CD4 counts were used to determine
CD4 slopes during treatment failure. CD4 counts were excluded from the
analysis if the concurrent viral load was not "stable." That is, if the VL
blipped up and subsequent VLs returned to the prior "stable" level, the CD4
count at the time of the blip would not be analyzed. It appeared that if the
VL "reset" to a stably higher level, CD4 counts would be used in this
analysis. 2596 CD4 counts were obtained to obtained CD4 slope during failure
from 628 patients in whom baseline pretreatment CD4 counts were known. These
patients were 90% male, 60% MSM, CD4 median 170/ul, mean VL 4.5 logs
(32,000), and on any therapy for a median of 4.1 years, on HAART for a median
of 2.2 years, and exposed to a median of 8 antiretrovirals. The take-home
message was that for any VL at failure, the CD4 slope was greater if the
subject was off antiretrovirals, and that despite failure the mean CD4 slope
per year was still positive (CD4 gain) if the VL was less than 4.0 logs
(10,000). Further, even when failing with VLs of 4.5 logs or greater, the
CD4 slope was roughly Ð20 cells/year, less than the Ð70 cells/yr seen in
untreated infection. Further, when examining the delta viral load from
setpoint (eg. 5 logs prior to therapy - 4 logs at failure = 1 log delta VL),
a delta VL of 2 logs or more predicted a positive CD4 cell slope (CD4 gain).
Numerous studies have shown the gradual accumulation of drug-resistance mutations when viremia is detectable. This process occurs more rapidly for single point mutations that confer high-level drug resistance, and when the level of viremia at failure is higher. However, decisions regarding about when to change therapy should take into account the continued benefit of partial suppression of viral replication (delta viral load).
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