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CROI 2011 Report - Selected Topics
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Eric S. Daar, M.D.
Chief, Division of HIV Medicine
Harbor-UCLA Medical Center
Professor of Medicine
The 18th Conference on Retroviruses and Opportunistic Infections provided the opportunity for a substantial amount of data to be reported on HIV treatment and pathogenesis. There were many important presentations at this meeting which substantially advanced the field of HIV medicine. This report will focus on safety and efficacy data related to treatment as prevention, the optimal time to initiate antiretroviral (ARV) therapy in those diagnosed with tuberculosis (TB) as well as new data related to first-line ARV therapy and neuropathogenesis.
3 HIGHLIGHTS From this Report:
"CNS involvement occurs early during the course of HIV infection and raises issues as to whether such damage supports early use of ARV therapy and whether the initiation of HIV-specific treatment is able to stabilize or reverse HIV-associated neurologic disease."
"treatment during primary and chronic infection resulted in a reduction in cellular activation. Compared to those started with chronic infection, patients started early had 4.8-fold lower level of the cellular reservoir as measured by proviral HIV DNA (p=0.0045), as well as significantly lower levels of cell-associated RNA"
"study of 124 neuroasymptomatic and 25 AIDS dementia complex patients who were clinically stable on ARVs and followed for two years (32).....showed despite selection of a neuroasymptomatic population on stable and effective ART there was a detectable increase in atrophy of all areas of the corpus callosum. Although these patients remained relatively stable, there were declines in learning and processing speeds which were weakly associated with progressive atrophy of the anterior midbody of the corpus callosum. These studies both suggest that neurodegenerative processes are continuing in otherwise clinically stable, mostly virologically suppressed patients, and such changes need to be monitored for and further investigated as patients live longer on ARV therapy."
Treatment as prevention
Efficacy of systemic pre-exposure prophylaxis in MSM. There has been little progress in developed or developing countries to reduce the risk of HIV transmission by strategies that require behavioral changes. This along with the slow progress towards the development of a preventative HIV vaccine has led to increasing investigation of biologic strategies to prevent transmission. During the last several months success has been seen using pre-exposure prophylaxis (PrEP). Most recently the iPrEx study reported the ability of tenofovir DF/emtricitabine (TDF/FTC) given once daily to reduce the risk of HIV transmission to men who have sex with men (MSM) by 44% (p=0.005), and greater than 90% in those with the highest levels of adherence (1). The iPrEx study enrolled 2499 HIV-seronegative MSM who were randomized 1:1 to once-daily TDF/FTC or placebo. At this meeting data was presented on an additional four months of follow-up which was accompanied by 31 more incident infections, 48 in the TDF/FTC and 83 the placebo group overall (p=0.002) (2). It was emphasized that the study population included very young MSM who outside of the two sites in the United States had adherence levels of less than 60%.
Systemic PrEP effect on bone mineral density and drug resistance. Other studies focused on the potential risks of systemic PrEP. Since TDF-containing regimens have been shown in HIV-infected individuals to be associated with reduction in bone mineral density (BMD) this was addressed in two studies of PrEP. One analyzed BMD as part of a double-blind safety trial of TDF versus placebo in approximately 200 HIV-uninfected MSM (3). Dual-energy x-ray absorptiometry (DEXA) was performed in 184 participants at baseline, 9 or 12 months, and 24 months. A substantial number had low BMD at baseline, predicted by the use of methamphetamines and poppers. In the longitudinal analysis by intent-to-treat, the TDF group had a 1.1% net decrease in mean BMD at the femoral neck (p=0.004), 0.8% net decrease at the total hip (p=0.003), and a nonsignificant decrease at the lumbar spine (p=0.11). It appears that most of the BMD decline was observed in the first 12-15 month with less decline thereafter. In a substudy of 503 iPrEx participants it was also seen that they had relatively low baseline BMD, Z score <-1 at lumbar spine and hip compared to the currently available standards (4). The serial DEXA scans performed at 24-week intervals showed that at the total hip there was a modest but significant difference in BMD change between the study arms at weeks 24 (-0.65; 95% CI: -1.03, -0.28, p=0.001) and 48 (-0.95; 95% CI: -1.56, -0.35, p=0.002), but not at 72 (-0.22; 95% CI: -1.0, 0.56, p=0.58). Data at the spine also showed a decrease at week 24 but only a trend toward a difference at weeks 48 (p=0.11) and 72 (p=0.052). The clinical relevance of these findings needs to be explored in extended follow-up of iPrEx as well as other TDF-containing PrEP studies being performed in other populations.
Another concern regarding PrEP is the potential to select for drug resistant virus in those that become infected while on treatment. In the published iPrEx paper no drug resistance was identified by population sequencing amongst those who became infected during the course of the study (1). It is noteworthy that all but three of the infected subjects had undetectable drug levels, with the other three having very low levels suggestive of extremely poor adherence. A new study presented at CROI used allele-specific PCR to detect very low levels of resistance that might have been selected for amongst those on TDF/FTC who became infected. The investigators reported no evidence of drug resistance even with this highly sensitive tool (5). This data is limited because adherence was poor amongst the failures. Consequently, this issue will need to be carefully explored during the rollout of systemic PrEP.
Intrarectal pre-exposure prophylaxis. Another recent success in the area of transmission came from the CAPRISA 003 study where pre- and post-vaginal intercourse use of tenofovir (TFV) 1% vaginal gel resulted in a 39% reduced risk of HIV transmission to heterosexual at-risk women (6). At this meeting a phase 1 trial (RMP-02/MTN-006) reported the results of a small study of systemic TDF and 1% TFV gel, the latter as a rectal microbicide (7). The study enrolled 18 HIV-uninfected men (n=14) and women (n=4). Rectal use of this hyperosmolar gel was found to be associated with complaints of lower gastrointestinal discomfort. While this would suggest that the current formulation of the gel may not be optimal for rectal use, the study did show that the gel was not associated with any mucosal injury, achieved local tissue levels 100-fold higher than that achieved with systemic TDF and those tissue biopsies were relatively resistant to ex vivo HIV infection.
First-line antiretroviral therapy
Baseline factors associated with response to ARVs. With many available ARV options it is increasingly important to individualize therapy. At CROI data was reported from a meta-analysis of AIDS Clinical Trials Group (ACTG) studies. The analysis combined data from studies of first-line therapy and assessed the relationship between race and virologic failure (8). The investigators showed that regardless of what the first-line regimen was, at 3 years of follow-up blacks had greater risk of virologic failure than whites, 45% versus 32%, respectively (p<0.001), with an overall 40% greater risk of virologic failure by Cox proportional hazards model. Risk of failure was also greater for those who were younger, had evidence of hepatitis coinfection, and not surprisingly reported poor adherence. This study was limited to a United States population and it was not possible to adjust for all potential confounders, particularly those related to baseline social factors.
Additional analyses were reported from the most recently completed large ACTG treatment-naïve study, A5202, which was not included in the above meta-analysis. A5202 randomized patients to abacavir/lamivudine (ABC/3TC) or TDF/FTC with efavirenz (EFV) or atazanavir plus ritonavir (ATV/r). This study previously reported a higher virologic failure rate amongst those given ABC/3TC, regardless of whether with ATV/r or EFV in those that had screening viral loads of at least 100,000 copies/mL (9), but not those with screening viral load of <100,000 copies/mL (10). An analysis was reported at this meeting to see whether the relationship was also seen in the total study population by baseline, rather than screening viral load and CD4 cell count. The previous results with screening viral load were in fact confirmed using baseline values. In addition, there was also a greater risk for virologic failure amongst the ABC/3TC group in those with lower CD4 cells at baseline (11). A related analysis addressed the relationship between sex, race, ethnicity and virologic failure in A5202. Similar to what has been seen in other studies, including the meta-analysis of previous ACTG studies, black race was associated with increased risk of virologic failure. In addition, women were found to be at higher risk of virologic failure than men when given ATV/r, regardless of NRTIs, and had better responses to EFV- than ATV/r-containing regimens (12). The latter observations have not been previously seen and will require further exploration and confirmation.
Cardiovascular events and ABC. In a study that is relevant to the use of ABC, the United States Food and Drug Administration reported the results of a meta-analysis assessing the relationship between ABC use and cardiovascular events. This study was prompted by concerns raised in the D:A:D study showing a strong association between ABC use and cardiovascular events, particularly amongst those with current or recent use of ABC and having multiple other cardiovascular risk factors (13). The FDA analysis included 9832 patients from 26 randomized-controlled trials from 1996-2010 and did not see an increased risk of myocardial infarctions in those given ABC (n=5028) versus other NRTIs (n=4804) (14). The study was limited by the relatively small number of events, short follow-up and the fact that it is not known how many of the subjects were at high risk for cardiovascular events.
Raltegravir as first-line therapy. The STARTMRK study previously demonstrated the safety and efficacy of TDF/FTC given with 400 mg of RAL twice-daily compared to EFV (15). At this meeting the 3 year follow-up of this study was reported showing continued efficacy with 75.4% of RAL and 68.1% of EFV patients having viral loads of <50 copies/mL (16). In addition, there continued to be less adverse events in the RAL group and both were noted to experience overall increases in fat as measured by DEXA scans. Despite the efficacy and tolerability of RAL, its use is somewhat limited by the need for twice-daily dosing. Based upon the fact that a phase 2b study demonstrated similar efficacy with once-daily dosing, the inability to define pharmacokinetic-pharmacodynamic relationship with this drug and the potential for prolonged binding of RAL to the pre-integration complex, the QDMRK phase III trial was designed (17). This study compared the approved 400 mg twice-daily dose of RAL to 800 mg given once-daily. This was to be a 96 week study but after 48 weeks it was found that while both study arms experienced high levels of virologic suppression, the once-daily regimen was inferior to twice-daily dosing, with the proportion <50 copies/mL being 83.2% and 88.9%, respectively, a difference of -5.7% (95% CI: -10.7, -0.83). The difference in virologic response rate also appeared to be considerably greater amongst those with higher baseline viral loads at the time of study entry. A pharmacokinetic substudy showed a higher virologic failure rate among those assigned once-daily RAL with lower trough levels, suggesting that the difference in response may be related to the pharmacokinetics of the drug. These results led to the study being stopped and the recommendation that RAL continue to be only used twice-daily.
Nucleoside analog reverse transcriptase inhibitor-sparing therapy.
Although commonly used NRTIs are generally well tolerated, there are concerns regarding potential long-term toxicity and there are individuals who do not tolerate them. For these reasons there continues to be interest in defining the safety and efficacy of regimens that do not include NRTIs. One previously reported study was the MONOI-ANRS 136 which compared continued therapy with NRTIs plus darunavir/ritonavir (DRV/r) versus DRV/r alone given twice-daily, with the option to switch to once-daily DRV/r after the first year. At this meeting the 96-week follow-up from this study was presented. Of the 225 patients that enrolled, 193 had 96 weeks of follow-up. By intent-to-treat analysis, 93.8% in the DRV/r only arm versus 90.6% in the NRTIs plus DRV/r group had viral loads <50 copies/mL (18). The results were similar for both arms with the exception being that there was a lower number on mono- than combination therapy that always had viral loads <50 copies/mL during follow-up, 59 vs. 70%, respectively (p=0.10). These results are consistent with others that have shown that compared to combination ARV therapy, ritonavir-boosted monotherapy is effective but more frequently associated with low levels of viremia, the significance of which is not known since resistance does not tend to emerge.
A novel NRTI-sparing regimen described at this meeting was a single-arm study, ACTG A5262, where treatment-naïve patients were given once-daily DRV/r (800/100 mg) plus RAL (400 mg twice-daily) over 52 weeks (19). Of the 112 patients enrolled, 17 had viral failure by week 24 (primary endpoint) and 28 by week 48, for an overall failure rate of 26% (95% CI: 19%, 36%). In addition to this being a somewhat higher rate of virologic failure than expected, concerns regarding potency of the regimen were raised by the fact that the risk for virologic failure was greater amongst those with lower baseline CD4 cells (p=0.008) and higher viral loads (p=0.002). Based upon this study, novel combinations should continue to be used with great caution pending the availability of more data.
First-line antiretroviral therapy in resource-limited setting. Two arms of the ACTG 5175 PEARL study were presented for the first time at this meeting. This study was primarily conducted in resource-limited countries with a small number being enrolled in the United States. The study originally had three study arms, zidovudine/lamivudine (ZDV/3TC) twice-daily with EFV, TDF/FTC once-daily with EFV or once-daily didanosine (ddI), 3TC plus ATV. The last study arm was previously reported and prematurely discontinued due to inferior virologic efficacy. At this meeting the data from EFV with either ZDV/3TC or TDF/FTC was presented. The overall efficacy showed similar virologic responses, although consistent with other studies there were a greater frequency of adverse events with ZDV/3TC than TDF/FTC-containing regimens (20).
Treatment during primary HIV infection. There were several studies that addressed the potential role of therapy during acute and early HIV infection. One such study compared virologic and immunologic assays performed on samples from patients that started ARVs within the first 6 months of infection (n=34) to another group that started on treatment at least two years after infection (n=32). The study showed that treatment during primary and chronic infection resulted in a reduction in cellular activation. Compared to those started with chronic infection, patients started early had 4.8-fold lower level of the cellular reservoir as measured by proviral HIV DNA (p=0.0045), as well as significantly lower levels of cell-associated RNA (p=0.035) (21). While these observations are of interest, the clinical relevance of these findings is not known.
Another study assessed the potential benefits of treatment during primary infection with 5 versus 3-drug regimens. This study randomized 40 patients identified within the first 6 months of infection to two NRTIs with DRV/r or ATV/r (n=14) or these three drugs with RAL and maraviroc (n=26) (22). The patients underwent detailed virologic and immunologic studies and at 48 weeks it was reported that while viral suppression was common and similar in both groups, the addition of two extra drugs was not associated with further reduction in inflammatory markers or viral measures as assessed by single copy assay, proviral cellular HIV DNA or cell-associated RNA. While further studies, including sampling of gut-associated lymphoid tissue and longer follow-up are ongoing, it appears that the reservoir of persistent infection is established early and is not influenced by intensification of early therapy.
A third study was a randomized-controlled trial to determine whether transient treatment during primary HIV infection would result in a lower viral set-point off therapy compared to those who were not initially started on ARVs. This study included 115 patients who were randomized to either be followed without ARVs or to start ARVs for 24 or 60 weeks with subsequent treatment interruption. Endpoints were viral load after 36 weeks off treatment and the need to initiate treatment based upon development of HV-related symptoms or CD4 cells <350 cells/uL. This is one of the few randomized-controlled trials designed to address this question, with the rationale being that early therapy may preserve HIV-specific immune responses which may enhance viral control off treatment. In fact, they found that there was a significantly lower viral set point in those who initiated and then discontinued ARVs compared to those that deferred treatment. Moreover, there was no difference in viral set point between those treated for 24 vs. 60 weeks (23). This data suggests that there may be virologic benefits associated with earlier treatment, and if so 60 is not any better than 24 weeks. Nevertheless, the benefits are transient and at a time where increasing attention is being given to the potential damage caused by any level of HIV replication it is not clear that this strategy could be justified in the current treatment era.
ARV therapy in patients with TB
A recent study showed the benefit of earlier initiation of ARV therapy in those diagnosed with opportunistic infections, in particular pneumocystis pneumonia (24). More recently related studies have illustrated similar benefits of early ARV therapy in those with tuberculosis. The CAMELIA study enrolled patients with <200 CD4 cells/uL to start ARVs within 2 weeks or 8 weeks of initiating TB treatment. This study population had a median CD4 cell count of 25 cells/uL and showed that there was a significantly greater risk of death amongst those who waited until 8 weeks to start ARVs (25). A second study called SaPiT enrolled patients with TB and <500 CD4 cells/uL, that had a median CD4 cell count of approximately 150 cells/uL. One of the three arms was prematurely discontinued because of higher risk of progression to AIDS or death in those who delayed starting ARVs until they completed their course of TB treatment (26). The other two study groups either started ARVs within approximately 4 weeks or 8-12 weeks after initiating TB treatment. For this comparison they found that overall there was no significant difference for the primary endpoint; however, in a prespecified analysis, patients with <50 CD4 cells/uL who started ART earlier had a 68% reduced risk of progression to new AIDS defining illness or death (p=0.06) (27). In contrast, no difference was seen between study groups for those with >50 CD4 cells/uL (p=0.34). The risk of IRIS was significantly higher for patients starting ART earlier, but this was not associated with increased mortality.
The STRIDE study (ACTG 5221) randomized 806 patients starting TB treatment who had <250 CD4 cells/uL to either initiate ARVs within 2 weeks or 8-12 weeks of TB therapy. The primary endpoint was week-48 all-cause mortality or new AIDS illnesses. The study population had a median CD4 count of 77 cells/uL and had no difference in primary endpoint at week 48 (p=0.45). In a prespecified analysis of patients with <50 CD4 cells/uL there was again a significantly greater risk of progression to AIDS or death amongst those who delayed initiation of ART until 8-12 weeks after starting TB treatment (p=0.02). Of note, there was no difference between study groups in secondary endpoints of CD4 cell increase, virologic suppression, and grade 3 or 4 adverse events. In contrast, there was an increased risk of IRIS in patients who started earlier ARV therapy.
These three randomized, controlled trials consistently show that HIV-infected patients who start TB treatment with <50 CD4 cells/uL should initiate ART during the first weeks. In contrast, for those with >50 CD4 cells/uL, it is less clear that a clinical benefit is associated with starting ART within the first 2 versus 8-12 weeks of TB treatment.
Neurologic complications of HIV infection
There have been increasing numbers of studies published and presented at major meetings that have attempted to identify the relationship between HIV, ARVs and central nervous system (CNS) disease. There were two studies at this meeting showing that HIV can affect the brain during the first days of infection. One such analysis focused on 20 Thai subjects identified during acute HIV infection that agreed to intensive neurologic testing including lumbar punctures and magnetic resonance spectroscopy (MRS) (29). It was shown that CSF HIV RNA was detectable in 14 of 17 evaluated patients, with virus detected as early as five days post estimated date of actual infection. In addition, there was evidence of inflammation in the cerebrospinal fluid (CSF) as assessed by neopterin and MCP-1 levels which correlated with CSF HIV RNA, p=0.008 and 0.009, respectively. Evidence of early CNS involvement was also noted by MRS with elevated choline/creatine ratios (marker of inflammation) compared to controls at basal ganglia (p=0.04) and occipital gray matter (p=0.07). Another cross-sectional study was presented by a group in Chicago that evaluated patients infected for less than one year and studied by volumetric measurements of the brain. Compared with controls, they found small but significant reductions in brain matter in the left (p=0.02) and right (p=0.04) cerebral cortex, along with significant enlargement of the third ventricle (p=0.04) (30). Together these studies suggest that CNS involvement occurs early during the course of HIV infection and raises issues as to whether such damage supports early use of ARV therapy and whether the initiation of HIV-specific treatment is able to stabilize or reverse HIV-associated neurologic disease.
Two analyses performed by the HIV Neuroimaging Consortium presented longitudinal data on CNS disease amongst subjects with chronic HIV infection on stable ARV therapy. The first study included 167 neuroasymptomatic patients with CD4 nadir of approximately 36 cells/uL who at study entry were mostly on suppressive ARV therapy with mean CD4 cells of nearly 300 cells/uL. Cross-sectional analyses at baseline demonstrated evidence of inflammation and neuronal loss by MRS with the latter correlating with neurocognitive impairment. After two years of longitudinal follow-up they found that 35% of subjects had developed AIDS Dementia Complex (ADC) stage ≥0.5 and 12% ≥1.0 (31). In a multivariate analysis, progression to mild disease (ADC stage ≥0.5) was predicted by decrease in N-acetyl aspartate (marker of neuronal damage) in the basal ganglia and an increase in myoinositol (marker of inflammation) in midfrontal cortex. In this analysis, progression to ADC stage ≥1.0 was only predicted by decrease in basal ganglia N-acetyl aspartate. Of note, progression was not related to other factors, including ARV CSF penetration effectiveness (CPE) scores. Another analysis from the same consortium assessed changes in corpus callosum in 124 neuroasymptomatic and 25 AIDS dementia complex patients who were clinically stable on ARVs and followed for two years (32). They showed despite selection of a neuroasymptomatic population on stable and effective ART there was a detectable increase in atrophy of all areas of the corpus callosum. Although these patients remained relatively stable, there were declines in learning and processing speeds which were weakly associated with progressive atrophy of the anterior midbody of the corpus callosum. These studies both suggest that neurodegenerative processes are continuing in otherwise clinically stable, mostly virologically suppressed patients, and such changes need to be monitored for and further investigated as patients live longer on ARV therapy.
References
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31. Navia B, et al. A longitudinal study of neurological injury in HIV-infected subjects on stable ART: The HIV neuroimaging consortium cohort study. 18th Conference on Retroviruses and Opportunistic Infections; February 27-March 2, 2011; Boston, MA. Abstract 56.
32. Tate D, et al. Progressive atrophy of the corpus callosum in HIV-infected patients on stable ART. 18th Conference on Retroviruses and Opportunistic Infections; February 27-March 2, 2011; Boston, MA. Abstract 443.
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