Table of Contents
A review of:
In the field of HIV therapeutics, blocking the earliest steps in the infectious life cycle of HIV represents a very attractive prospect. For HIV to gain entry into host CD4+ T cells, it must first bind to both the CD4+ receptor and one of two chemokine receptors -- either CCR5 or CXCR4 -- via viral envelope glycoproteins. This process leads to conformational changes in viral glycoproteins and ends with the fusion of viral and cell membranes. As such, the process of viral entry provides a novel therapeutic target against HIV. One subclass of HIV entry inhibitors making impressive headway consists of agents known as CCR5 antagonists or CCR5 inhibitors that bind to and shield the chemokine receptors from HIV binding.
Every chemokine antagonist currently in development is specific to only one of the two chemokine receptors -- that is, to either CCR5 or CXCR4, not both. In general, HIV preferentially uses the CCR5 coreceptor during early infection. HIV viral types that use CXCR4 evolve at later disease stages. HIV viral types that use only CXCR4 tend to be rare; it is more common to find mixtures of R5-using and X4-using viruses within a viral population, rather than just X4-using virus, or virus (i.e., dual-tropic virus) that is capable of using either of the coreceptors.
Just as it is important to assess for the presence of antiretroviral drug resistance to help guide the selection of a treatment regimen containing only active agents, so too is it important to establish viral tropism, or (i.e., determining which chemokine receptor HIV is using during infection), to help determine which type of chemokine antagonist to include in a patient's regimen.
With the impending arrival of maraviroc (UK-427,857; with the expected brand name of Celsentri) as the first CCR5 antagonist to be approved by the U.S. Food and Drug Administration (FDA), researchers endeavor to find a means of predicting viral tropism without the need for complex and expensive phenotype assays. Additionally, information regarding tropism may generally be useful for all patients with HIV to determine the natural history of HIV infection and the timing of treatment interventions. For example, in individuals who are receiving a CCR5 antagonist, tropism information may be used to trigger discontinuation of this drug class.
In AIDS Clinical Trials Group (ACTG) study A5211, the use of vicriviroc (SCH 417690, SCH-D), an investigational CCR5 antagonist, was evaluated in treatment-experienced individuals with R5-only virus. Results from the study were presented at the XVI International AIDS Conference in Toronto in 2006.1 Data published in the Feb. 15, 2007, issue of Clinical Infectious Diseases by Timothy J. Wilkin et al2 looked at the results of the 391-patient study to evaluate the characteristics associated with the presence of a particular viral tropism.
As with a number of previously published epidemiological studies, 3-6 which have mainly been conducted in treatment-naive individuals, specific factors associated with R5 usage by HIV were not identified. Dual/mixed-tropic virus and X4-only virus were identified in individuals who had high as well as low CD4+ cell counts, and in those with low as well as high viral loads.
In keeping with previous studies, the researchers found that lower CD4+ cell counts were associated with a higher prevalence of dual/mixed-tropic virus, although dual/mixed-tropic virus was found to be common among patients at all CD4+ cell count strata. The dual/mixed-tropic group had a significantly lower median CD4+ cell count at screening than the R5-only group (103 cells/mm3 vs. 170 cells/mm3; P < .001). No other factors associated with tropism were identified in this cohort.
The observed frequency of both dual/mixed-tropic virus and X4-tropic virus was higher in this study than in two larger epidemiological studies performed in treatment-naive individuals that were published in the Journal of Infectious Diseases in 2005.3,4 Of the 391 individuals with coreceptor phenotype results available, 46% had dual/mixed-tropic virus and 4% had X4-tropic virus only.
Some small studies previously suggested that treatment with conventional antiretroviral agents may drive the emergence of X4-tropic virus in the HIV population. Because the current study was exclusively performed in treatment-experienced patients, the high prevalence of dual/mixed-tropic and X4-tropic virus that was observed is consistent with this view.
In addition to these findings, the study also points to a key problem with the performance of the Monogram Biosciences tropism assay that was used for screening patients for this study, as well as for the maraviroc development program as a whole. At the time this program was running, the turnaround time on the assay typically ranged from four to six weeks. Of the 391 individuals screened for the A5211 clinical study, 197 (50%) were identified as having only R5 virus on their screening blood sample.
However, when the individuals who entered A5211 had the assay repeated at their baseline visit, when they commenced their new antiretroviral regimen, 10% of 118 individuals who were originally identified as having only R5 virus were subsequently found to have dual/mixed-tropic virus. Clinical results from the study indicated that individuals who had dual/mixed-tropic virus had a poorer response to vicriviroc-containing therapy than individuals who remained only R5 tropic at baseline.1
Similar data were reported in the phase 3 program for maraviroc.7,8 The study investigators noted that the change in coreceptor status for this subset of individuals "likely represents variability of the assay in testing samples with low-level dual-tropic or X4-using variants, rather than a true change in coreceptor use," since the timing between the two evaluations was relatively short. However, they cannot exclude the possibility that a shift in viral tropism occurred between the time of screening and the time of therapy initiation.
The Bottom Line
Viral tropism cannot be reliably determined by treatment history or laboratory parameters; specific tropism testing is required. X4-tropic virus may be more common in the presence of low CD4+ cell counts and in persons with greater treatment experience. These findings suggest that CCR5 antagonists may be best used early in the treatment sequence.Long-term body composition and metabolic changes in antiretroviral naive persons randomized to protease inhibitor-, nonnucleoside reverse transcriptase inhibitor-, or protease inhibitor plus nonnucleoside reverse transcriptase inhibitor-based strategy. JC Shlay, G Bartsch, G Peng, J Wang, C Grunfeld, CL Gibert, F Visnegarwala, SS Raghavan, Y Xiang, M Farrough, HE Perry, D Kotler, WM El-Sadr, for the Terry Beirn Community Programs for Clinical Research on AIDS. Journal of Acquired Immune Deficiency Syndromes. April 15, 2007;44(5):506-517.
The prevalent chronic diseases of aging, including diabetes mellitus, cardiovascular disease and the metabolic syndrome, may be more common in people with HIV than in age-matched and sex-matched controls in the general population. Data support the concern that antiretroviral therapy, and possibly specific drug or regimen choices, may contribute to the premature onset of these diseases or increase their severity. Indeed, insulin resistance, dyslipidemia, lipoatrophy and lipohypertrophy have all been associated with antiretroviral use.
To better get to the bottom of this issue, investigators from the CPCRA FIRST (Community Programs for Clinical Research on AIDS Flexible Initial Retrovirus Suppressive Therapies) study team sought to assess changes in metabolic parameters and body composition among 422 antiretroviral- naive patients who were randomized to start therapy with either a protease inhibitor (PI; n = 141), a non-nucleoside reverse transcriptase inhibitor (NNRTI; n = 141) or a PI + an NNRTI (n = 140) -- each in combination with two nucleoside reverse transcriptase inhibitors (NRTIs).9
The most commonly used PI in both the PI and PI + NNRTI arms was nelfinavir (NFV, Viracept; 61%), followed by PIs boosted with ritonavir (RTV, Norvir; 24%) and indinavir (IDV, Crixivan; 12%). Most participants in the NNRTI arm received efavirenz (EFV, Sustiva, Stocrin; 63%), whereas nevirapine (NVP, Viramune) and efavirenz use was fairly evenly split for patients in the PI + NNRTI arm (49% and 50%, respectively).
Every four months for a median of 62 months, patients had their body composition measured and fasting blood collected for lipid analysis. At baseline, patients had a mean age of 38 years, 78% were male, and 73% were nonwhite (60% black, 10% Hispanic). The mean baseline viral load was 5.0 log10 copies/mL, and the mean CD4+ cell count was 215 cells/mm3.
Data on the effects of the NRTI backbones used in this study -- stavudine (d4T, Zerit) + didanosine (ddI, Videx) versus abacavir (ABC, Ziagen) + lamivudine (3TC, Epivir) -- have previously been reported.10 According to the current analysis, the PI + NNRTI group demonstrated greater increases in triglycerides and low-density lipoprotein (LDL) cholesterol when compared with the PI and the NNRTI groups after the first month of treatment (both P values < .005), with no differences observed between the PI and NNRTI approaches.
These differences tended to persist over the long term (Table 1). High-density lipoprotein (HDL) cholesterol increased significantly more with NNRTIs than with PIs (P < .005). Similar increases in insulin and insulin resistance were observed with all three strategies. In addition, changes in total and regional body composition were observed, but these values did not differ by strategy.
The anthropometry data from FIRST suggest that the choice between either a PI or an NNRTI does not play a significant role in limb fat loss. Previously, the ACTG 384 trial suggested that nelfinavir-based therapy may independently contribute to limb fat loss as compared with efavirenz-based therapy.11
More recently, in ACTG 5142, patients receiving lopinavir/ritonavir (LPV/r, Kaletra) were less likely to experience limb fat loss of 20% or more than efavirenz recipients over 96 weeks.12 This may have been due to greater increases in fat mass after PI therapy was initiated.
Fat recovery studies such as MITOX (Relationship Between Fatigue and Mitochondrial Damage in Patients With HIV/AIDS) and RAVE (Renal Atherosclerotic Revascularization Evaluation) have indicated that PI use versus NNRTI use does not influence limb fat recovery. 13,14
Overall, this leaves the impression that the choice between a PI or NNRTI is certainly not as critical to limb fat loss as the selection of the NRTI backbone. In fact, PIs and NNRTIs may not play a role in limb fat loss at all.
Regarding lipids and insulin resistance, the data over five years from FIRST point to substantial and sustained rises in pro-atherogenic particles and the emergence of insulin resistance in a sizeable subset of patients, which sets the scene for the premature emergence of diabetes mellitus and cardiovascular disease.
A regimen consisting of a PI + NNRTI appears to be particularly prone to producing lipid disturbances, according to this study and ACTG 5142. NNRTIs may be preferred for long-term therapy due to the favorable HDL-cholesterol effects. Use of stavudine has been associated with insulin resistance, as shown in FIRST10 but also in MACS (Multicenter AIDS Cohort Study),15 the D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) study16 and most recently healthy volunteers. 17 Some PIs, at least in healthy-volunteer studies, may also trigger insulin resistance. Thus, glucose disposal may take a double hit with some regimens.
The Bottom Line
Multiple antiretroviral agents contribute to metabolic and morphologic changes, which are likely to substantially increase the risk and shorten the time to onset of future cardiovascular events and diabetes mellitus. The specific agents included in an antiretroviral regimen appear to be important factors influencing the degree of metabolic and morphological changes observed during long-term therapy.
A review of:
Ritonavir-boosted darunavir (TMC114, Prezista) has recently been approved for use in treatment- experienced individuals,18,19 and the drug is also under investigation for use in treatment-naive populations. The approval of darunavir is based on two randomized studies20 and a safety cohort study,21 all conducted in individuals with at least one primary PI mutation. These studies are known as the POWER (Performance of TMC114/r When Evaluated in Triple-Class- Experienced Patients With PI Resistance) studies.
POWER 1 and 2 included treatment-experienced patients with at least one primary PI mutation and a viral load above 1,000 copies/mL. All participants received an optimized background regimen, consisting of nucleoside analog agents chosen with the assistance of phenotypic and genotypic resistance tests, together with the option of using enfuvirtide (T-20, Fuzeon). Patients were then randomized to receive darunavir + ritonavir, dosed at either 400/100 mg once daily, 800/100 mg once daily, 400/100 mg twice daily or 600/100 mg twice daily, or comparator PIs (CPIs; excluding tipranavir [TPV, Aptivus] and other investigational PIs).
The primary POWER endpoint by intent-to-treat analysis compared the proportions of patients achieving a viral load reduction of at least 1.0 log10 copies/mL from baseline -- the current, standard FDA hurdle for accelerated approval.
POWER 1, conducted mainly in Europe and Australia, included 318 patients with a mean baseline viral load of 4.48 log10 copies/mL and a median CD4+ cell count of 179 cells/mm3. The PIs used in the CPI arm were lopinavir (LPV; 46%), saquinavir (SQV, Invirase; 38%), (fos)amprenavir (APV, Agenerase; FPV, 908, Lexiva, Telvir; 25%), atazanavir (ATV, Reyataz; 21%) and indinavir (2%). Only 29% of patients in the CPI arm received PI boosting with ritonavir.
The 24-week results of POWER 1, reported in the Feb. 19 issue of AIDS, are broadly indicative of the observations in all three POWER studies. Importantly, 48-week data22 from these studies show that the responses observed at week 24 are durable over time, with no new or unexpected safety events.
According to the 24-week results of POWER 1, more darunavir recipients (69% - 77%) than CPI recipients (25%) reached the primary endpoint of at least a 1.0-log10 viral load reduction from baseline (P < .001).
According to the new treatment goal of achieving undetectable HIV-1 RNA in treatment-experienced patients, 43% to 53% of darunavir + ritonavir patients achieved a viral load of less than 50 copies/mL, compared with only 18% of individuals in the CPI arm (P < .001).
Moreover, darunavir + ritonavir produced greater mean increases in CD4+ cell count in comparison with CPIs (68 - 124 vs. 20 cells/mm3; P < .05).
The incidence of adverse events was similar between the darunavir + ritonavir and the CPI treatments, as well as across the different doses of darunavir. Darunavir + ritonavir 600/100 mg twice daily demonstrated the highest virologic and immunologic responses. As a result, this dose was chosen for further development and has subsequently gained FDA approval.
These studies provide an introduction to darunavir, but they do not necessarily tell us the best way to use this new PI. Highly treatment-experienced individuals entering the study did particularly well when they had fewer protease mutations, higher CD4+ cell counts and lower viral loads at baseline and when they could combine darunavir with multiple active agents, particularly first use of enfuvirtide.
These guiding principles of managing treatment-experienced patients are consistent across multiple studies in this population, including the TORO (T-20 vs. Optimized Regimen Only) studies of enfuvirtide and the RESIST (Randomized Evaluation of Strategic Intervention in Multi-Drug Resistant Patients With Tipranavir) studies of tipranavir.23-25
Although enfuvirtide and tipranavir have largely remained restricted to heavily treatment-experienced patients, darunavir appears to be destined for wider use.
Once-daily darunavir + ritonavir dosing in POWER 1 resulted in good virologic responses (e.g., HIV-1 RNA < 50 copies/mL: 43% - 48%), albeit the 600/100 mg twice-daily dose produced slightly higher response rates (HIV-1 RNA < 50 copies/mL: 53%). Darunavir + ritonavir 800/100 mg once daily is now under investigation for use in treatment-naive individuals.
The POWER 1 data suggest that darunavir has a tolerability profile similar to or better than the most common CPIs used in the salvage setting (i.e., lopinavir/ritonavir, fosamprenavir + ritonavir).
Most notably, darunavir recipients showed similar or better tolerability with regard to gastrointestinal events, liver function abnormalities and lipid disturbances. This suggests that darunavir may be considered as an alternative agent in individuals currently receiving these PIs and experiencing bothersome adverse events.
The Bottom Line
Darunavir represents the new PI standard of care for use in PI-experienced individuals. In this setting, the drug is best used when it can be combined with multiple active agents.
Good tolerability to the agent also suggests that darunavir may be an alternative to other widely used PIs in less treatment-experienced individuals, or it may be an attractive replacement agent when toxicity to alternative PIs is reported. Darunavir also demonstrates the potential for once-daily dosing -- something that is currently being investigated in treatment-naive individuals.
A review of:
Although highly active antiretroviral therapy (HAART) is often extremely effective at suppressing HIV replication to undetectable levels, such therapy is not curative. The problem, it seems, is that a latent reservoir of HIV persists despite antiretroviral therapy -- a reservoir in which HIV can later become activated and begin replicating. This reservoir is of critical importance during HIV treatment, as it may be the key obstacle standing in the way of HIV eradication and a cure.
This brief report26 published by Siliciano and colleagues in the March 15 issue of the Journal of Infectious Diseases follows up on another report27 suggesting that short-term treatment with valproic acid might accelerate the decay of the latent reservoir of HIV in individuals on antiretroviral therapy.
Valproic acid is often used to treat seizures, migraines and bipolar disorder. The agent is also able to increase gene expression. Given this latter function, it is hypothesized that valproic acid may be able to stimulate latent HIV-infected cells to render them susceptible to HAART.
The current study included nine individuals who had been on HAART for an average of 26.1 months and who all had suppression of viremia below 50 copies/mL. All patients were also receiving valproic acid and had been for a mean of 21.9 months. When initially sampled, the average length of time that the patients had been receiving both a suppressive antiretroviral regimen and valproic acid was 12.7 months.
Latent HIV-infected cells were readily detected in all patients treated with valproic acid and HAART, and the levels of these cells were comparable to the levels previously seen in patients receiving HAART alone (geometric mean frequency: 1.05 vs. 0.82 infectious units per million [IUPM]).28
Repeat measurements were made in seven of the nine patients an average of 5.1 months after the initial sampling to assess for additional viral decay. These findings revealed no further decay of the latent reservoir and instead showed about a two-fold increase (geometric mean frequency: 2.2 IUPM).
Only two patients showed additional reservoir decay; the frequencies remained the same in one patient and actually increased in four patients.
The Bottom Line
Valproic acid appears to have no effect on the decay of the latent reservoir of HIV in patients on HAART.Survival of persons with and without HIV infection in Denmark, 1995-2005. N Lohse, A-B E Hansen, G Pedersen, G Kronborg, J Gerstoft, HT Sørensen, M Vth, N Obel. Annals of Internal Medicine. January 16, 2007;146(2):87-95.
In the developed world, HIV infection is now commonly regarded as a potentially manageable and chronic condition analogous to diabetes mellitus. However, like people with diabetes mellitus, there continues to be a relative increase in the news of morbidity and mortality among people with HIV infection regardless of effective antiretroviral therapy. Knowing the expected survival of HIV-infected individuals is of interest to public health, as well as to the individuals suffering with such disease.
This study from Denmark29 sought to determine survival in the HIV population relative to age-matched and sex-matched individuals in the general Danish population. The study included 3,990 HIV-infected individuals who received care in Denmark from 1995 to 2005. These individuals were matched with an average of 95 HIV-uninfected individuals from the general population, giving a total population of 379,872 controls matched by sex, age and geographic residence.
As with other countries in the developed world, the advent of effective antiretroviral therapy has had a substantial and dramatic impact on HIV-related deaths between 1995 and 2005 in Denmark. For individuals 25 years of age, the overall median survival for HIV-infected individuals was 19.9 years, whereas the median survival for individuals in the general population was 51.1 years. Importantly, however, the median survival for HIV-infected individuals increased to 32.5 years during the late HAART era (2000 - 2005). In accord with these findings, the mortality rate from conditions related to HIV infection decreased from 76% in 1995 to 1996, to 57% in 1997 to 1999, and to 43% in 2000 to 2005.
Coinfection with hepatitis C was noted to be an important contributor to mortality. For example, the expected survival of 25-year-old HIV-infected persons without hepatitis C coinfection in the late HAART period was 38.9 years. This value was shortened to 32.5 years when individuals with hepatitis C coinfection were included in the analysis.
The study provides excellent evidence of the dramatic impact that successful antiretroviral therapy has had on the survival of persons with HIV infection. However, it also provides evidence of a survival gap between HIV-infected and HIV-uninfected individuals, suggesting that there is room for improvement -- even in countries where there is a well-funded national health service with treatment and medicines provided free at the point of delivery.
The study also emphasizes the importance of avoiding hepatitis C coinfection given the impact that this virus has on survival in persons with HIV. Improving treatment for people infected with HIV and hepatitis C can be seen as a specific target for improving the management of HIV-infected individuals as a whole.
The Bottom Line
Persons with HIV infection who receive HAART can be expected to survive for a prolonged period -- more than 30 years. This underlines the importance of assessing the long-term safety of antiretroviral medications and further investigating the way in which antiretroviral agents may contribute to the prevalence of the chronic diseases of aging.
This article was provided by TheBodyPRO.com. It is a part of the publication HIV JournalView.