New Data on the Treatment of Antiretroviral-Experienced Patients

Hopkins HIV Report 2006 Sep; 18(5):1,12-15

Gregory M. Lucas, M.D., Ph.D.
Johns Hopkins

After a slow start early in the week of the IAC, the Toronto meeting wound up with an 18-abstract, 3-hour, late-breaker extravaganza session. In the mix was a healthy serving of data pertaining to the treatment of antiretroviralexperienced patients. Early data emerged from the Africa-based DART study corroborating the report from the SMART trial earlier this year showing that structured treatment interruptions place patients at increased risk of disease progression. A number of studies addressed the potential role of lopinavir/ritonavir monotherapy [see Gallant J, this issue, Antiretroviral Therapy: Intial Therapy], 48-week results of the POWER-1 and -2 studies were presented, and promising data on the use of CCR5 co-receptor inhibitors were presented.

Lesson From DART and SMART: Don’t Plan to Stop Once You Start

The Development of Antiretroviral Trial in Africa (DART) is a large-scale clinical trial being conducted at several sites in Africa that is primarily designed to compare a less intensive with a more intensive monitoring strategy in patients initiating highly active antiretroviral therapy (HAART) with advanced disease. Nested within this study is a substudy assessing the feasibility and safety of structured treatment interruptions (STI). Participants who had attained a CD4 count of >300 cells/mm³ after 48 to 72 weeks of HAART were randomized to continuous treatment versus cycled STI (12-week on/12-week off ). At the late-breaker session, J. Hakim presented results from this substudy, which has been halted due to a higher risk of disease progression in the STI arm than in the continuous therapy arm [Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. THLB0207].

Unlike typical Western HIV clinical trials, three-quarters of the 813 participants in the DART STI sub-study were women. Clinical variables were well matched in the two arms, and participants had a median pre-HAART nadir CD4 cell count and a median current CD4 cell count of 130 and 360 cells/mm³, respectively. The most commonly used HAART regimen was zidovudine, lamivudine, and tenofovir. The median follow-up in the study was 51 weeks, with participants in the STI arm spending just 50% of follow-time taking HAART, as intended by the cycling strategy. The trial was halted by the data and safety monitoring committee in June 2006 when the STI arm was found to have a 2.7-fold higher risk of death or new WHO category 4 events (p=0.007) than the continuous therapy arm. The difference was driven by morbidity, not mortality: The mortality rate was low overall and was similar in the two study arms (1.3% vs. 1.0% annually in STI and continuous HAART, p=0.7). Candida esophagitis was the condition that accounted for a large proportion of the difference in the event rates between the two arms.

Preliminary results from the post-mortem on the Strategies for Management of Antiretroviral Therapy (SMART) trial were reported in two oral abstracts at a session devoted to STI strategies. SMART was a multinational study in which 5,472 participants who were doing well on HAART were randomized to continuous HAART versus CD4-guided STI. According to the STI protocol, treatment was interrupted when the CD4 count was >350 cells/mm³, and was restarted when the CD4 count was <250 cells/mm³. The SMART trial was halted in January 2006 when the STI arm was found to have a 2.6-fold higher risk of death or opportunistic condition than the continuous HAART arm [El Sadr W, et al. Conf Retroviruses Opportunistic Infect. 2006 Feb 5-8;13th: Abstract No. 106LB], a relative risk that was remarkably similar to that found in the DART study.

J.D. Lundgren presented a follow-up analysis from SMART using time-updated (i.e., the latest available) CD4 cell counts and HIV RNA values. The results indicated that differences in the time spent at various CD4 and HIV RNA strata explained much of the difference in clinical event rates between the two arms [Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. WEAB0203]. Not surprisingly, the risk of disease progression was strongly linked to the time-updated CD4 counts and viral loads, irrespective of study arm. Equally unsurprising was that the subjects in the STI arm spent much more time with lower CD4 counts and higher viral loads than participants in the continuous treatment arm. For example, 69% of STI participant time was spent with a CD4 count <400 cells/mm³, compared to just 22% in the continuous therapy arm. When the analysis was adjusted for these differences, much of the difference in clinical outcomes between the arms was explained.

What remains remarkable, however, is the relatively high CD4 cell counts at which clinical events occurred. For example, in subjects who experienced a clinical event, the median CD4 counts closest to the event were 417 cells/mm³ and 617 cells/mm³ in STI and continuous therapy arms, respectively. It is also worth noting that the higher risk of disease progression in the STI arm can not be readily attributed to frequent failure to restart participants’ HAART at the protocoldefined threshold of 250 cells/mm³. Only 3.1% of participant follow-up time in the STI was spent with a CD4 count <200 cells/mm³, compared to 0.8% in the continuous therapy arm. While differences in current CD4 cell counts between the arms explained a substantial proportion of the risk difference, there was also evidence of excess risk in the STI arm at the highest CD4 cell count strata. As shown in Table 1, the clinical event rates were much higher at lower CD4 cell counts, but were similar in the STI arm and the continuous HAART arms in these lower strata. In contrast, the relative risk of clinical events was over 2-fold higher in the STI arm versus the continuous HAART arm at the highest CD4 cell counts.

At higher CD4 cell counts the differences in current HIV RNA levels tended to be larger between STI and continuous therapy subjects than in the lower CD4 count strata. This makes sense because continuous therapy patients with the highest CD4 counts were most likely to be doing well on HAART and to have suppressed viral loads. In contrast, participants in the STI arm with high CD4 cell counts would be the most likely be off therapy, according the CD4-guided protocol, and hence have high viral loads. The finding that the STI strategy was associated with excess risk in the highest CD4 strata may reflect viral load-mediated immune impairment that not is captured by the current CD4 cell count. Waafa El-Sadr presented subgroup analyses from SMART [Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. WEAB0203]. The increased risk of clinical progression associated with STI compared to continuous therapy was generally consistent across sub-groups analyzed, and no subgroup was identified in which STI was beneficial. Consistent with the Lundgren presentation, El-Sadr reported that the beneficial effects on disease progression with continuous therapy compared to STI was most evident in patients with the highest CD4 counts and undetectable HIV RNA levels at baseline (i.e., subjects who were doing the best on HAART at enrollment). The lesson here is that those who have gained the most from HAART have the most to lose by stopping.

One intriguing finding from sub-group analysis was that the relative risk of nonopportunistic condition-associated deaths in the STI arm compared to the continuous therapy arm was significantly higher in black than nonblack participants. Some have speculated that immune activation or other adverse consequences of interrupting HAART may mediate progression of non-HIV associated disease, and that blacks may be more susceptible to these effects than other racial/ethnic groups. Additional investigations underway on the SMART data set may shed light on this issue.

At the STI session, Maggiolo presented 4-year clinical follow-up from the BASTA study (Italian for “enough!”) [Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. WEAB0202]. This small study (n=114), which was not HAART versus CD4-guided STI. According to the STI protocol, treatment was interrupted when the CD4 count was >350 cells/mm³, and was restarted when the CD4 count was <250 cells/mm³. The SMART trial was halted in January 2006 when the STI arm was found to have a 2.6-fold higher risk of death or opportunistic condition than the continuous HAART arm [El Sadr W, et al. Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 106LB], a relative risk that was remarkably similar to that found in the DART study.

J.D. Lundgren presented a follow-up analysis from SMART using time-updated (i.e., the latest available) CD4 cell counts and HIV RNA values. The results indicated that differences in the time spent at various CD4 and HIV RNA strata explained much of the difference in clinical event rates between the two arms [Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. WEAB0203]. Not surprisingly, the risk of disease progression was strongly linked to the time-updated CD4 counts and viral loads, irrespective of study arm. Equally unsurprising was that the subjects in the STI arm spent much more time with lower CD4 counts and higher viral loads than participants in the continuous treatment arm. For example, 69% of STI participant time was spent with a CD4 count <400 cells/mm³, compared to just 22% in the continuous therapy arm. When the analysis was adjusted for these differences, much of the difference in clinical outcomes between the arms was explained.

What remains remarkable, however, is the relatively high CD4 cell counts at which clinical events occurred. For example, in subjects who experienced a clinical event, the median CD4 counts closest to the event were 417 cells/mm³ and 617 cells/mm³ in STI and continuous therapy arms, respectively. It is also worth noting that the higher risk of disease progression in the STI arm can not be readily attributed to frequent failure to restart participants’ HAART at the protocoldefined threshold of 250 cells/mm³. Only 3.1% of participant follow-up time in the STI was spent with a CD4 count <200 cells/mm³, compared to 0.8% in the continuous therapy arm.

While differences in current CD4 cell counts between the arms explained a substantial proportion of the risk difference, there was also evidence of excess risk in the STI arm at the highest CD4 cell count strata. As shown in Table 1, the clinical event rates were much higher at lower CD4 cell counts, but were similar in the STI arm and the continuous HAART arms in these lower strata. In contrast, the relative risk of clinical events was over 2-fold higher in the STI arm versus the continuous HAART arm at the highest CD4 cell counts.

At higher CD4 cell counts the differences in current HIV RNA levels tended to be larger between STI and continuous therapy subjects than in the lower CD4 count strata. This makes sense because continuous therapy patients with the highest CD4 counts were most likely to be doing well on HAART and to have suppressed viral loads. In contrast, participants in the STI arm with high CD4 cell counts would be the most likely be off therapy, according the CD4-guided protocol, and hence have high viral loads. The finding that the STI strategy was associated with excess risk in the highest CD4 strata may reflect viral load-mediated immune impairment that not is captured by the current CD4 cell count.

Waafa El-Sadr presented subgroup analyses from SMART [Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. WEAB0203]. The increased risk of clinical progression associated with STI compared to continuous therapy was generally consistent across sub-groups analyzed, and no subgroup was identified in which STI was beneficial. Consistent with the Lundgren presentation, El-Sadr reported that the beneficial effects on disease progression with continuous therapy compared to STI was most evident in patients with the highest CD4 counts and undetectable HIV RNA levels at baseline (i.e., subjects who were doing the best on HAART at enrollment). The lesson here is that those who have gained the most from HAART have the most to lose by stopping.

One intriguing finding from sub-group analysis was that the relative risk of non-opportunistic condition-associated deaths in the STI arm compared to the continuous therapy arm was significantly higher in black than non-black participants. Some have speculated that immune activation or other adverse consequences of interrupting HAART may mediate progression of non-HIV associated disease, and that blacks may be more susceptible to these effects than other racial/ethnic groups. Additional investigations underway on the SMART data set may shed light on this issue.

At the STI session, Maggiolo presented 4-year clinical follow-up from the BASTA study (Italian for “enough!”) [Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. WEAB0202]. This small study (n=114), which was not powered to detect differences in clinical outcomes, found low and similar rates in disease progression in patients randomized to CD4-guided STI or continuous HAART. The STI guidance protocol in BASTA was also substantially more conservative than that use in DART or SMART. To be included in the study, subjects had to have a CD4 count >800 cells/mm³ and HIV RNA <50 c/mL on HAART, and therapy was restarted in the STI arm when the CD4 count fell below 400 cells/mm³. Over prolonged follow-up, disease progression occurred in 3 participants assigned to continuous therapy (2 deaths and one case of cervical cancer) and no subjects assigned to STI. A longer duration of the first treatment interruption in the STI arm was strongly correlated with higher nadir CD4 cell count, as has been noted by others. The small sample size of BASTA is not sufficient to tell us that this safety-conscious STI protocol does not pose higher risk to participants than continuous HAART. Additionally, the proportion of the in-treatment HIV-infected population that would be eligible for STI under this protocol is quite small.

Em-POWER-ed

Forty-eight week results from the pooled POWER-1 and -2 studies of ritonavir-boosted darunavir (DRV) in highly treatmentexperienced subjects were reported by Lazzarin [Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. TUAB0104]. Twenty-four week results of these trials have been presented previously and were sufficiently impressive to earn FDA approval of DRV in June of this year. The similarly designed POWER-1 and POWER-2 were phase IIb studies in which triple-class experienced subjects were treated with an optimized background regimen (OBR) and were randomized to 1 of 4 doses of DRV or to a comparator protease inhibitor (CPI), which was selected by the investigator prior to randomization. Participants had a median of 8 protease resistance mutations at baseline, had received nucleoside reverse transcriptase inhibitors (NRTIs) for a median of 8.5 years, and most had been treated with enfuvirtide previously. Results were presented only for 124 participants in the CPI arm and 131 participants in the arm that received DRV 600 mg bid plus RTV 100 mg bid, which was the dose selected for further development and approved by the FDA. The results strongly favored DRV, with 61% achieving an HIV RNA reduction of ≥1 log₁₀ c/mL from baseline at week-48, versus just 15 % in the CPI arm (P<0.001). A phenotypic susceptibility fold-change to DRV of >10 at baseline was associated with decreased response to DRV, and a fold-change of >40 appeared to obviate the possibility of achieving viral suppression in either arm.

CCR5 Inhibitors Offer Next Ray of Hope for Patients with Highly Resistant Virus

In AIDS Clinical Trials Group (ACTG) 5211, 118 patients who were failing their current regimen and had R5-tropic virus at screening added either placebo or 1 of 3 doses of vicriviroc (VCV, a CCR5 coreceptor inhibitor under development) to their failing regimen for 14 days [Gulick R, et al. Abstract THLB0217]. Following the 14-day addition phase, all subjects substituted an OBR for their previously failing regimen. At 14 days the median HIV RNA decrease was approximately 1 log₁₀ c/mL in the VCV arms versus no change in the placebo arm (p<0.001). At week 24, 11% of subjects in the control arm had HIV RNA <400 c/mL compared to a range of 43% to 53% in the VCV arms. The lowest dose of VCV (5mg daily) was discontinued due to trends for a higher virologic failure rate and more frequent co-receptor switching in this arm. Although participants were required to have R5-tropic virus at screening, 10 participants had R5/X4 dual/mixed tropic virus at enrollment. The average HIV RNA change at 24 weeks was -0.77 log₁₀ c/mL in R5/X4 subjects compared to -1.83 log₁₀ c/mL in subjects with exclusively R5-tropic virus at enrollment. Five malignancies were diagnosed in VCV patients (2 non-Hodgkin’s lymphomas, 2 Hodgkin’s lymphomas, and 1 gastric adenocarcinoma) and 2 malignancies occurred in placebo recipients (1 case each of cutaneous and perianal squamous cell carcinoma). The potential association of malignancy with VCV is unclear, but is being followed closely.

R5-tropic virus is the infecting phenotype in the vast majority of HIV-infected individuals. However, tropism switches to X4 or dual/mixed tropism in approximately 50% of individuals during the natural history of infection. In the absence of effective therapy, this co-receptor tropism switch is correlated with increased viral load, more rapid CD4 decline, and a higher risk of clinical disease progression and death, although the causal pathway of this association has not been established. The possibility of accelerating disease progression with CCR5 inhibitors by selecting X4-tropic virus, either de novo or from pre-existing X4 variants that are below the limit of detection of current assays, has always been a concern for this drug class.

Mayer and coworkers addressed this concern to some degree in a study in which multi-class experienced patients with X4-tropic or dual/mixed-tropic virus were treated with 1 of 2 doses of maraviroc (MVC, another CCR5 co-receptor inhibitor under development) or placebo plus OBR [Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. THLB0215]. The placebo and MVC groups experienced similar HIV RNA declines of approximately 1 log₁₀ c/mL by week-24. However, CD4 cell increases were somewhat greater in the MVC arms than in the placebo arm, even in subjects who had only X4-tropic virus at the time of virologic failure. This study provides some reassurance that using a CCR5 inhibitor in patients with dual/mixed-tropic virus, which will undoubtedly occur, will not subject those patients to more rapid immunologic deterioration by selecting X4- over R5-tropic virus.

Transmitted Drug Resistance Holding Steady at 9%

The SPREAD study is a European surveillance cohort designed to track the prevalence of transmitted drug resistant in newly-diagnosed treatment-naïve HIV-infected individuals. In the 2002-2003 SPREAD cohort of 1,083 subjects, drug-resistant virus was detected in 9%, with 5.4% having NRTI resistance, 3.0% having PI resistance, and 2.6% having NNRTI resistance, and just 0.7% having multi-class resistance [Wensing AM, et al. Int Conf AIDS. 2006 Aug 13-18;16:Abstract No. TUAB0101]. In comparison with data from previous European surveillance studies conducted since 1996, the overall prevalence of drug resistance appears stable, with a decreasing prevalence of NRTI resistance, and trends toward increasing or stable prevalence of PI and NNRTI resistance. It’s worth mentioning that the absence of an upward trend in transmitted drug resistance in Western Europe may be affected by the influx of HIV-infected immigrants from Africa, where transmitted drug resistance would be less likely than in developed countries with longstanding access to HAART.

Interestingly, in the SPREAD cohort, the prevalence of resistance was similar in subjects with documented HIV infection in the previous 12 months and in those with longer or unknown duration of HIV infection (10.6% vs. 8.7%, respectively). This supports other studies that have suggested that transmitted drug resistance mutations in treatment-naïve individuals may remain detectable in plasma longer than in patients with treatment-related drug resistance who have stopped therapy; resumably when resistant mutants are transmitted, wild-type virus is not present . Reversion to wild-type virus requires back-mutation rather than outgrowth of pre-existing wild-type variants, a more timeconsuming process. If true, this supports the recommendation for the routine clinical use of genotypic resistance tests in newly diagnosed treatment-naïve patients, regardless of their likely duration of infection.

Conclusion

While treatment interruptions will continue to occur and may be needed in many HIVinfected patients over decades of treatment, data continue to amass from large well-conducted clinical trials suggesting that using STI as a strategy to lower cost or reduce drug toxicity places patients at higher risk of disease progression. These data also imply that delaying the initiation of HAART in patients with earlystage disease may not be as safe as we once believed. The impressive early results of DRV in highly drug-resistant participants in the POWER studies have been borne out to 48 weeks. Finally, CCR5 inhibitors offer hope for heavily treatment-experienced patients in need of a new drug class for salvage therapy.

2006-09-10
HHR-2006-09-02

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