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19th Conference on Retroviruses and Opportunistic Infections Report: prevention/PrEP, eradication, the brain, new HIV antiretroviral drugs
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March 5-8, 2012
Seattle, WA
Eric S. Daar, M.D.
Chief, Division of HIV Medicine
Harbor-UCLA Medical Center
Professor of Medicine
David Geffen School of Medicine
Prevention Strategies
Several very important studies were presented at the 19th CROI related to pre-exposure prophylaxis (PrEP). The first study was Partner PrEP that had previously reported early data demonstrating that compared to placebo oral tenofovir DF (TDF) and TDF/emtricitabine (TDF/FTC) taken once daily by HIV-uninfected individuals with infected partners resulted in significant reduction in the risk of acquiring HIV. The study enrolled 4758 HIV-infected individuals and their sexual partners from Kenya and Uganda with monthly testing and counseling of the HIV-uninfected, and quarterly visits for the HIV-infected partners (1). The study started in July 2008 and in July 2011 the Data Safety Monitoring Board (DSMB) recommended stopping the placebo arm. The final results presented at this meeting included 82 incident infections that occurred after randomization, 17 in the TDF arm, 13 in the TDF/FTC arm and 52 in the placebo group. This translated into a 67% reduction in the risk of transmission with TDF and 75% with TDF/FTC compared with placebo, with statistically significant protection seen for both men and women. There was some increased nausea and fatigue early on with the active drugs versus placebo but overall the agents were well tolerated with no difference in creatinine levels. They further assessed sexual behaviors and found that unsafe sexual practices actually declined during the course of study. While the results were convincing, it has become increasingly clear that adherence will be a critical factor for the success of PrEP. In fact, in this study despite patients reporting greater than 95% adherence with study products, data from a case cohort study assessing drug levels suggested otherwise (2). The substudy measured drug levels in 30 individuals with incident infection compared to 200 randomly selected uninfected participants. They found detectable levels of tenofovir in more than 80% of the controls while in only 25-30% of those that became infected during the study. This data suggests that the actual activity of daily TDF and TDF/FTC is probably considerably better than what was seen in the study.
In April 2011 there was a press release stating that the FEM-PrEP trial that started in July 2009 was being stopped at the recommendations of the DSMB because of futility. The actual results of this study were presented at this meeting for the first time (3). FEM-PrEP enrolled 3900 high risk HIV-uninfected women and randomized them to once daily TDF/FTC versus placebo with a planned 52 weeks of follow-up. At the time the study was stopped 2120 HIV-uninfected African women were enrolled with 68 incident infections, 33 in the TDF arm and 35 amongst placebo recipients. Use of TDF/FTC was associated with increased gastrointestinal side effects but not in creatinine levels. The early press release said that those given active drug had significantly higher rates of pregnancy, a finding that was not confirmed at the time of the final analysis. Needless to say there was a great deal of interest in understanding why iPrEX, an early PrEP study in men who have sex with men, and Partners PrEP demonstrated significant protection while this study showed none. Poor adherence initially seemed like an unlikely explanation since it was shown by patient self-report to be approximately 95%, and by pill count >85%. However, drug levels were assessed in a subset of patients as a biologic assessment of adherence. Shockingly, detectable tenofovir levels were seen in <40% of those tested, and <30% amongst those randomized to active drug. Clearly this level of adherence would make it impossible for this study to demonstrate any efficacy of TDF/FTC for HIV prevention in this patient population. Moreover, this data illustrates the importance of adherence as well as the difficulty in making accurate assessments of therapy-taking behavior.
Another study addressed the potential of a new rectal microbicide as a strategy for PrEP. A previously reported study demonstrated poor tolerability when the hyperosmolar tenofovir 1% gel used in the vaginal microbicide studies was used rectally. Data was presented at this meeting from MTN-007 which used a new reduced glycerin formulation of 1% tenofovir gel which has approximately 25% the osmolality of the original product (4). This gel was used in 65 HIV-uninfected men and women and was found to be well tolerated and deemed acceptable for use by more than 85% of the study subjects. There is already a phase 2 study planned with this product in men who have sex with men.
In conclusion, the use of systemic PrEP continues to demonstrate a protective effect in HIV-uninfected individuals that take the drug. In addition, there is increasing clarity as to why there have been discordant results between studies, in particular those seen in FEM-PrEP. It is also clear that the utility of PrEP for prevention will be highly dependent upon adherence, which will be a challenging obstacle to the use of this prevention strategy. Future studies will need to focus on means in which to enhance and measure adherence both in clinical trials of PrEP, as well as if it is to be used in clinical practice.
Antiretroviral Therapy
Two phase 3 trials were presented at the 19th CROI that were designed to assess the safety and efficacy of the fixed dose combination of TDF plus FTC with the new integrase inhibitor, elvitegravir, pharmacologically boosted by cobicistat, called the "Quad." One study compared the Quad with fixed dose combination TDF/FTC/efavirenz (TDF/FTC/EFV) (5). This was a placebo-controlled study that enrolled 700 patients without transmitted drug resistance with a primary endpoint of percent with plasma HIV RNA <50 copies/mL at 48 weeks using FDA recommended Snapshot (intent-to-treat) analysis with a pre-specified noninferiority margin of 12%. The study population had a median CD4 of 390 cells/uL with plasma HIV RNA 4.7 log10 copies/mL. The overall proportion <50 copies/mL for the Quad versus TDF/FTC/EFV was 88 and 84%, respectively, with a difference of 3.6% (95% CI -1.6, 8.8) demonstrating noninferiority. Similar efficacy was seen across all subgroups including those with high baseline plasma HIV RNA and by sex. There was a significantly greater increase in CD4 cells in the Quad than TDF/FTC/EFV group, 239 versus 206 cells/uL, although the clinical relevance of this difference is not known. Resistance testing was performed in 14 Quad failures with 8 having resistance, all with NRTI resistance and 7 of 8 having integrase resistance, most often the E92Q mutation. From a safety perspective there was more nausea and diarrhea with the Quad and more neurologic symptoms with TDF/FTC/EFV. In addition, there were more discontinuations due to rash on TDF/FTC/EFV and for renal changes on Quad, although both occurred in less than 2% of patients. TDF/FTC/EFV had greater increases in total cholesterol and LDL than the Quad, although no difference was seen in the total to HDL cholesterol ratio. Consistent with other data suggesting that cobicistat alters renal tubular handling of creatinine there was an early change in creatinine in the Quad arm that was relatively stable after 4 weeks of follow-up.
The other study of Quad compared it with TDF/FTC plus ATV plus ritonavir (ATV/r) (6). This study enrolled 700 patients and demonstrated noninferiority of Quad with the protease-inhibitor containing regimen with the percent undetectable at 48 weeks being 90% and 87%, respectively, with a difference of 3.0% (95% CI -1.9, 7.8). The main difference in adverse events was increased frequency of hyperbilirubinemia in the ATV/r-containing arm. There was an increase in creatinine during the first four weeks in both study arms, but to a greater degree with the Quad, likely related to the effect of cobicistat on renal tubular handling of creatinine rather than a direct nephrotoxic effect. Although the changes observed in creatinine with the Quad are probably of little clinical relevance, this will raise some issues in the clinic where clinicians will likely need to ignore early changes and monitor closely for trends after the first 4 weeks of therapy. The Quad is being reviewed for approval from the FDA and if approved will be the third one-pill, once per day regimen approved for the initial treatment of HIV infection. Moreover, it will be the first integrase-containing regimen available in this simplified form, and will provide a one-pill once-per-day option that has similar virologic efficacy to TDF/FTC/EFV.
Another integrase inhibitor in development is dolutegravir, which appears to be active at low doses without pharmacologic boosting making it a good candidate for coformulation. At this meeting the 96 week data was presented from the phase 2b study demonstrating very high levels of virologic efficacy at all doses, with similar virologic responses to TDF/FTC/EFV (7). This drug is already in phase 3 trials in treatment naïve and experienced patients. Another study of a novel drug was a 10-day monotherapy study of GS-7340, a prodrug of tenofovir (8). This agent has been shown to have good absorption with rapid entry and high concentrations in lymphoid tissue. The study presented at the 19th CROI administered 25 and 40 mg once daily for 10 days to HIV-infected patients and showed up to an approximate 1.5 log10 copy/mL reduction in plasma HIV RNA which exceeded that seen with the TDF comparator arm. In addition, this was achieved with much lower levels of drug in the plasma and 7 to 20-fold higher level of the tenofovir-diphosphate form in peripheral blood mononuclear cells. The hope for this compound is that it will be given at a much lower dose than TDF, and therefore be amenable to coformulation with a protease inhibitor, as well as the possibility that the lower plasma levels will be associated with less toxicity. The true efficacy and safety will need to be shown during the course of further development which is already underway for this compound.
Neurologic Manifestations of HIV Infection
There were numerous presentations and sessions devoted to neurologic complications of HIV disease. This is an area that has received renewed attention during the past several years due to the recognition that a substantial number of people with good plasma viral suppression have measureable levels of cognitive deficits, so called HIV-associated neurologic disorder (HAND). While true AIDS dementia is relatively rare in the current era, mildly symptomatic and even asymptomatic HAND, the latter only detected with careful neurologic testing has been described in excess of 30% of virologically suppressed patients. Recent research has focused on defining the significance of this problem and whether anything can be done about it when detected. In fact, many clinicians have argued that what is being identified in these studies is not readily apparent amongst the majority of patients in their practice. And even if the high prevalence of this condition is true, many have questioned the clinical relevance of these findings. There were two studies showing that these deficits may prove to be clinically important. First, Heaton and colleagues evaluated serial neuropsychiatric testing performed in the CHARTER longitudinal study and found that HAND detected by careful neuropsychologic testing in otherwise asymptomatic patients (n=84) and those with mild neurocognitive disorder (n=57) can be associated with a greater risk of neurocognitive decline compared to those presenting without neuropsychological abnormalities (n=246), p=0.0002 (9). Further data from the same cohort identified neurocognitive decline in 22.7% and showed in a multivariate analysis that predictors of decline included being Hispanic, having severe comorbidity, being off antiretroviral therapy and having low CD4 counts, p=0.0001 (10). Another unanswered question relates to the clinical relevance of detectable HAND in those who are otherwise asymptomatic. In order to address this, investigators included instruments that assessed employment capacity and medication management (11). These investigators found that amongst 175 asymptomatic HAND patients scores in the area of employment capacity were similar to those with mild neurocognitive disorder (n=44) and significantly lower than those without HAND (n=345), p<0.0001. This is some of the best data thus far suggesting that mildly symptomatic or asymptomatic HAND may have important clinical implications for our patients.
Other studies attempted to address the relationship between the presence of HAND and evidence of virologic escape in the central nervous system (CNS). There is also ongoing research attempting to determine whether certain drugs penetrate the CNS better than others, and whether such differences are clinically relevant. Since it is not possible to sample brain tissue, most research in this area has been limited to cerebrospinal fluid (CSF) sampling. There were several large studies that assessed the frequency of detectable CSF HIV RNA in those with fully suppressed plasma virus. Letendre and colleagues demonstrated that among 413 patients with longitudinal follow-up with at least 3 plasma samples each (n=2207 visits), 33% of plasma and 12% of CSF had HIV RNA levels above the level of detection with approximately 6% being positive in CSF when undetectable in the plasma. (12). They found in a multivariable analysis that the strongest predictor of having detectable CSF HIV RNA was having detectable plasma RNA. Other factors associated with increased risk of having detectable CSF HIV RNA were lower CD4 cells, higher CD8 cells, the presence of a CSF pleocytosis, having lower CSF penetration effectiveness score and receiving a protease inhibitor. Another study assessed CSF HIV RNA levels collected sequentially from patients with undetectable plasma HIV RNA who did not have CNS opportunistic processes or evidence of progressive neurologic decline. They found that in 53 patients 12 (22%) had a positive CSF HIV RNA at least once, but often were undetectable on subsequent measurements (13). Collectively these data suggest that virologic escape in the CSF occurs but the clinical relevance remains uncertain, may be difficult to interpret and/or act upon. Another small retrospective study evaluated 10 patients with neurologic symptoms that were found to have detectable CSF HIV RNA either in the presence of undetectable plasma HIV RNA or at a level that was at least 10-fold greater than that measured in the plasma. In these individuals 6 of 7 that had CSV HIV genotyped demonstrated evidence of drug resistance mutations and 8 of 9 that adjusted therapy reported improvement in their neurologic symptoms (14). This data is consistent with other small previously published studies, but remains small and less than definitive for guiding clinical practice.
In conclusion, there are increasing numbers of publications and presentations at scientific meetings attempting to better characterize the neurologic complications of HIV. Despite new data and incremental advances in our understanding of how HIV affects the brain there remains much to learn. In particular, further research is still needed to define the clinical relevance of mild and asymptomatic HAND, what the predictors of having/developing HAND are, and what is the natural history in those on suppressive antiretroviral therapy. Moreover, it remains unproven that specific antiretroviral agents will be more effective for the treatment and/or prevention of HIV-associate neurologic disease. Finally, studies are needed to determine what the best approach is to identify and manage patients with mild and asymptomatic HAND.
Eradication studies
Enhanced treatment options for HIV-infected individuals have shifted the focus towards developing strategies for HIV eradication. While this area of research remains in its infancy, there has been considerable interest in strategies to reduce the size of the resting memory CD4 T-cell reservoir, felt to be a major obstacle to eradication, and to better understand what led to the possible "cure" observed in the "Berlin patient" that received an allogeneic stem cell transplant from a donor that was homozygous for the CCR5Δ32 mutation. There were several presentations at this meeting addressing these issues.
Several studies intensively evaluated the effect of antiretroviral therapy initiated during acute HIV infection has on the size of the cellular reservoir. One such study compared the reservoir as measured by HIV DNA as total, integrated and 2-long terminal repeat (LTR) in those treated during acute infection (n=9), chronic infection (n=26) and amongst elite controllers (n=37) (15). It was not surprising that HIV DNA was detectable regardless of how early therapy was initiated and amongst the elite controllers. Nevertheless, they did find that the levels were significantly lower in those treated during acute infection than during chronic. Moreover, the levels in the early treatment group were similar to the elite controller. While early treatment did not eliminate the reservoir, even amongst those with 10 years of follow-up, it is conceivable that the success of any future strategies to target the reservoir may be more successful in those with a smaller reservoir, such as those initiating therapy during acute infection. Further studies assessed the effect chemotherapy and chemotherapy with autologous stem cell transplant had on the size of the viral reservoir. One study simply assessed the effect ablative chemotherapy had on the viral reservoir (16). In this case they identified 10 patients enrolled in an ACTG longitudinal cohort study, ALLRT, who underwent chemotherapy for AIDS-related lymphoma while on suppressive ART. Using stored peripheral blood mononuclear cells (PBMCs) and plasma they looked to see if there was a change in plasma HIV RNA using a highly sensitive assay as well as total HIV DNA and 2-LTR circles before and after chemotherapy. The median time from pre- to post-chemotherapy sampling was 432 days, with no apparent change in any of the measures. While this study is small and chemotherapeutic regimens were variable, it certainly suggests that fairly intensive chemotherapy had little or no measurable effect on the HIV reservoir. Another study assessed the effect conditioning and autologous hematopoietic stem cell transplant had on the HIV reservoir (17). This was a cross-sectional study that included 10 patients who received transplants for Hodgkin's or Non-Hodgkin's lymphoma with follow-up sampling done a mean of 1334 days after transplantation. They found that using sensitive measurements of plasma HIV RNA and cellular DNA that there was persistence of virus in virtually all patients. It is notable that this situation was considerably different than the Berlin patient. For example, this was autologous rather than allogeneic transplant which means that some viral infected cells could have been reinfused. In addition, there was no need for immunosuppressive therapy, total body irradiation and no graft versus host occurred, all of which could have influenced the outcomes. Finally, the Berlin patient received stem cells from a person with the protective CCR5Δ32 genotype.
Replicating the experience of the Berlin patient is challenging and implementing it in any way is prohibitively expensive and dangerous. Consequently, other strategies are being pursued to alter a patient's cells so that they do not express CCR5 and are therefore not susceptible to R5 virus. One such approach is using Zinc Fingers nuclease modified autologous CD4+ T cells. Such an experiment was performed using an Ad5/35 chimeric vector to introduce the Zinc Finger nuclease into the patient's own CD4+ T-cells, expanding this cell population and then infusing them back into the virologically suppressed patients; 6 with CD4 >450 cells/uL and 15 with suboptimal immunologic recovery (CD4<500 cells/uL) (18). They found that a single infusion of 0.5-3.0 x 1010 cells was safe and well tolerated. There was also an increase in CD4 cell count and improvement in CD4:CD8 ratio that was greatest in those with higher CD4 cells and persisted during the approximate 1 year of follow-up. They further showed that the modified cells persist at a level of approximately 2% for up to a year and were trafficking into lymphoid tissue in the gut. Finally, there were 6 patients that interrupted therapy after infusion of the modified cells. In all cases there was a rebound in virus followed by a decline to levels approximating or perhaps somewhat lower than their pre-treatment set point. Notably, one patient had viral load decline to undetectable levels prior to reinitiating ART. In retrospect it was determined that this individual was heterozygous for the CCR5Δ32 genotype. While these results demonstrate a good safety profile and some promising immunologic results, future studies will likely need to demonstrate convincing virologic suppression if this treatment is to continue to move forward in clinical development.
Another strategy being pursued to reduce the cellular HIV reservoir is to induce latently infected cells to express virus with the hope that this will lead to clearance of this cell population. A leading approach to this is to inhibit histone deacetylase (HDAC) which appears to be a major factor in maintaining viral latency. A single dose pilot study used suberoylanilide hydroxamic acid (SAHA), called vorinostat, a drug currently licensed for the treatment of cutaneous T-cell lymphoma. The study was designed to assess whether this HDAC inhibitor could induce viral expression from latently infected resting memory CD4+ T cells (19). The investigators used a novel assay to sensitively detect changes in cell-associated RNA expression in resting memory cells after the single dose of vorinostat. This intensive study required patients undergo leukopheresis before and after treatment and showed in all six patients that there was indeed a significant increase in cell-associated HIV RNA expression. The findings from this study are consistent with that of others suggesting that HDAC inhibitors have the potential to target latently infected resting CD4+ T cells. Future studies will need to expand upon these observations and determine whether the use of SDAC inhibitors will result in an actual decay in the reservoir. The importance of this was illustrated by data presented at this meeting that used an in vitro model of latency and showed that SDAC inhibitor-induced viral expression from resting cells in the absence of a CTL response may not result in a decay of this reservoir (20).
In conclusion, the HIV research agenda has increasingly shifted towards the goal of viral eradication and/or functional cure. It is clear that a great deal of fundamental research is needed before any major advances can occur towards this goal. There were some excellent examples of areas of research underway to meet these objectives; however, as is often the case the new data mostly raises more questions that need to be addressed by further investigation. We can all look forward to more work in this area being presented at future meetings.
References:
1. Baeten J, et al. ARV PrEP for HIV-1 prevention among heterosexual men and women. 19th CROI 2012, Seattle, WA Abst. #29.
2. Donnell D, et al. Tenofovir disoproxil fumarate drug levels indicate PrEP use is strongly correlated with HIV-1 protective effects: Kenya and Uganda. 19th CROI 2012, Seattle, WA Abst. #30.
3. Van Damme L, et al. The FEM-PrEP trial of emtricitabine/tenofovir disoproxil fumarate (Truvada) among African women. 19th CROI 2012, Seattle, WA Abst. #32LB.
4. McGowan I, et al. MTN-007: A phase I randomized, double-blind, placebo-controlled rectal safety and acceptability study of tenofovir 1% gel. 19th CROI 2012, Seattle, WA Abst. #34LB.
5. Sax P, et al. Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate has non-inferior efficacy and favorable safety compared to efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naïve HIV-1+ subjects. 19th CROI 2012, Seattle, WA Abst. #101.
6. DeJesus E, et al. Week 48 results of an ongoing global phase 3 study comparing elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate with atazanavir/ritonavir-boosted plus emtricitabine/tenofovir disoproxil fumarate in treatment-naïve HIV-1+ subjects showing efficacy, safety, and pharmacokinetics. 19th CROI 2012, Seattle, WA Abst. #627.
7. Stellbrink, H-J, et al. Dolutegravir in combination therapy exhibits rapid and sustained antiviral response in ARV-naïve adults: 96-week results from SPRING-1 (ING112276). 19th CROI 2012, Seattle, WA Abst. #102LB.
8. Ruane P, et al. GS-7340 25 mg and 40 mg demonstrate superior efficacy to tenofovir disoproxil fumarate 300 mg in a 10-day monotherapy study of HIV-1+ patients. 19th CROI 2012, Seattle, WA Abst. #103.
9. Heaton R, et al. Asymptomatic mild HIV-associated neurocognitive disorder increases risk for future symptomatic decline: A CHARTER Longitudinal Study. 19th CROI 2012, Seattle, WA Abst. #77.
10. Heaton R, et al. Prevalence and predictors of neurocognitive decline over 18 to 42 months: A CHARTER Longitudinal Study. 19th CROI 2012, Seattle, WA Abst. #474.
11. Blackstone K, et al. How "asymptomatic" is HIV-associated asymptomatic neurocognitive impairment? 19th CROI 2012, Seattle, WA Abst. #497.
12. Letendre S, et al. Longitudinal correlates of HIV RNA levels in 2207 CSF specimens. 19th CROI 2012, Seattle, WA Abst. #473.
13. Eden A, et al. Longitudinal follow-up of detectable HIV-1 RNA in CSF in subjects on suppressive ART. 19th CROI 2012, Seattle, WA Abst. #488.
14. Peluso M, et al. Discordance between plasma and CSF HIV in virologically controlled patients presenting with neurologic symptoms. 19th CROI 2012, Seattle, WA Abst. #489.
15. Buzon M, et al. Treatment of early HIV infection reduces viral reservoir to levels found in elite controllers. 19th CROI 2012, Seattle, WA Abst. #488.
16. Cillo A, et al. Impact of chemotherapy for AIDS-related lymphoma on residual viremia and cellular HIV-1 DNA in patients on suppressive ART. 19th CROI 2012, Seattle, WA Abst. #353.
17. Cillo A, et al. Plasma viremia and cellular HIV-1 DNA persist despite autologous hematopoietic stem cell transplantation for AIDS-related lymphoma. 19th CROI 2012, Seattle, WA Abst. #154.
18. June C, et al. Induction of acquired CCR5 deficiency with Zinc Finger Nuclease-modified autologous CD4 T cells (SB-728-T) correlates with increases in CD4 count and effects on viral load in HIV+ subjects. 19th CROI 2012, Seattle, WA Abst. #155.
19. Archin N, et al. Administration of vorinostat disrupts HIV-1 latency in patients on ART. 19th CROI 2012, Seattle, WA Abst. #157LB.
20. Shan L, et al. Elimination of the latent reservoir for HIV-1 requires induction of CTL responses. 19th CROI 2012, Seattle, WA Abst. #153.
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