TAG HIV Basic Science, Vaccines, and Cure Project Blog

Maxed Out: Treatment Intensification Studies Report No Effect on Residual HIV Levels or Immune Activation

Scientists continue to wrestle with the question of whether combination antiretroviral therapy (ART) completely suppresses HIV replication in most recipients. The development of ultra-sensitive “single copy” viral load tests (which can measure down to 0.3 HIV RNA copies in a milliliter of blood) has revealed that most individuals with levels below 50 copies show evidence of persistent residual viral RNA. There are two potential (non-exclusive) sources: long-lived, chronically infected cells containing integrated viral DNA which produce RNA copies either intermittently or continuously—such cells would be impervious to the effects of current antiretroviral therapies—or low-level HIV replication, in which new RNA copies are produced which go on to infect other cells. In the latter case, intensifying ART with additional drugs would be predicted to reduce the amount of residual viral load and the number of cells containing integrated HIV DNA.

A slew of new papers (abstracts below) describe the results obtained in several different treatment intensification trials. The results add to the evidence that, in the majority of individuals, ongoing low-level HIV replication is not the source of residual HIV RNA, and nor is it the major driver of immune activation in individuals on ART. Most prior studies of treatment intensification have produced similar results, with just a couple of notable exceptions. In one small trial involving intensification with raltegravir there was a transient increase in a piece of HIV’s genetic code called a 2-LTR circle in around 1/3 of participants, which suggests the drug may have been blocking new rounds of infection in these individuals. Another similar trial produced evidence that the addition of raltegravir may have reduced HIV replication and immune activation in a specific part of the gut (the terminal ileum). But the preponderance of evidence now favors chronically infected cells as the primary source of residual viral load on ART, highlighting the importance of designing strategies to identify, target and eliminate this persistent HIV reservoir.

J Infect Dis. (2011) doi: 10.1093/infdis/jir667

First published online: October 21, 2011

Raltegravir Treatment Intensification Does Not Alter Cerebrospinal Fluid HIV-1 Infection or Immunoactivation in Subjects on Suppressive Therapy

Viktor Dahl1, Evelyn Lee2, Julia Peterson2, Serena S. Spudich2,a, Idris Leppla2, Elizabeth Sinclair3, Dietmar Fuchs4, Sarah Palmer1 and Richard W. Price2

1Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet and Swedish Institute for Infectious Disease Control, Stockholm, Sweden

2Department of Neurology

3Department of Medicine, University of California, San Francisco

4Division of Biological Chemistry, Biocentre, Innsbruck Medical University, Austria

Abstract

Background. Despite suppression of plasma human immunodeficiency virus type 1 (HIV-1) RNA by antiretroviral therapy to levels below clinical assay detection, infection and immune activation may persist within the central nervous system and possibly lead to continued brain injury. We hypothesized that intensifying therapy would decrease cerebrospinal fluid (CSF) infection and immune activation.

Methods. This was a 12-week, randomized, open-label pilot study comparing addition of the integrase inhibitor raltegravir to no treatment augmentation, with an option for rollover to raltegravir. CSF and plasma were analyzed for HIV-1 RNA using a single-copy assay. CSF and blood immune activation was assessed by neopterin concentrations and CD4+ and CD8+ T-cell surface antigen expression.

Results. Primary analysis compared 14 intensified (including rollovers) to 9 nonintensified subject experiences. Median HIV-1 RNA levels in all samples were lower in CSF (<.3 copies/mL) than in plasma (<.9 copies/mL; P < .0001), and raltegravir did not reduce HIV-1 RNA, CSF neopterin, or CD4+ and CD8+ T-cell activation.

Conclusions. Raltegravir intensification did not reduce intrathecal immunoactivation or alter CSF HIV-1 RNA levels in subjects with baseline viral suppression. With and without raltegravir intensification, HIV RNA levels in CSF were very low in the enrolled subjects. 

Clin Infect Dis. (2011) doi: 10.1093/cid/cir721

First published online: October 19, 2011

Short-course Raltegravir Intensification Does Not Increase 2 Long Terminal Repeat Episomal HIV-1 DNA in Patients on Effective Antiretroviral Therapy

Guillaume J. Besson1, Deborah McMahon1, Frank Maldarelli2, and John W. Mellors1

1Division of Infectious Diseases, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

2National Cancer Institute, Frederick, Maryland

TO THE EDITOR—Controversy exists about whether human immunodeficiency virus type 1 (HIV-1) replication persists in patients receiving effective antiretroviral therapy. Residual viremia can often be detected in such patients by sensitive quantitative polymerase chain reaction assays, but the source of this viremia is unknown [1]. Possibilities include ongoing cycles of HIV-1 replication, long-lived HIV-1–infected cells that continuously or intermittently produce virus, or both. If residual plasma viremia is derived from ongoing HIV-1 replication, intensification of an effective regimen with another potent antiretroviral drug should lower viremia. Such treatment intensification studies have been conducted with different classes of antiretroviral agents (nucleoside reverse-transcriptase inhibitors, nonnucleoside reverse-transcriptase inhibitors, protease inhibitors, and the integrase inhibitor raltegravir), and none has shown reduction in residual viremia [ …

JAIDS Journal of Acquired Immune Deficiency Syndromes:

POST ACCEPTANCE, 11 November 2011

doi: 10.1097/QAI.0b013e31823fd1f2

No Effect of Raltegravir Intensification on Viral Replication Markers in the Blood of HIV-1-infected Patients Receiving Antiretroviral Therapy

Gandhi, Rajesh T.; Coombs, Robert W.; Chan, Ellen S.; Bosch, Ronald J.; Zheng, Lu; Margolis, David M.; Read, Sarah; Kallungal, Beatrice; Chang, Ming; Goecker, Erin A.; Wiegand, Ann; Kearney, Mary; Jacobson, Jeffrey M.; D'Aquila, Richard; Lederman, Michael M.; Mellors, John W.; Eron, Joseph J.; for the AIDS Clinical Trials Group (ACTG) A5244 team

Published Ahead-of-Print

Abstract

Background: Controversy continues regarding the extent of ongoing viral replication in HIV-1-infected patients on effective antiretroviral therapy (ART). Adding an additional potent agent, such as raltegravir, to effective ART in patients with low-level residual viremia may reveal whether there is ongoing HIV-1 replication.

Methods: We previously reported the outcome of a randomized, placebo-controlled study of raltegravir intensification in patients on ART with HIV-1 RNA <50 copies/mL that showed no effect on residual viremia measured by single copy assay (SCA). We now report the effects of raltegravir intensification in that trial on other potential measures of ongoing HIV-1 replication: 2-LTR HIV-1 circles, total cellular HIV-1 DNA and T cell activation.

Results: Of 50 patients tested, 12 (24%) had 2-LTR-circles detected at baseline. Patients who were 2-LTR-positive had higher plasma HIV-1 RNA and HIV-1 DNA levels than 2-LTR-negative individuals. At week 12 of raltegravir intensification, there was no change from baseline in 2-LTR circles, in total HIV-1 DNA or in the ratio of 2-LTR circles to total HIV-1 DNA. There was also no change in markers of T cell activation.

Conclusions: In HIV-1-infected individuals on effective antiretroviral therapy, we find no evidence of ongoing viral replication in the blood that is suppressible by raltegravir intensification. The results imply that raltegravir intensification alone will not eradicate HIV-1 infection.

AIDS:

POST ACCEPTANCE, 14 November 2011

doi: 10.1097/QAD.0b013e32834e8955

Effect of raltegravir intensification on HIV proviral DNA in the blood and gut mucosa of men on long-term therapy: a randomized control trial

Chege, Duncan; Kovacs, Colin; La Porte, Charles; Ostrowski, Mario; Raboud, Janet; Su, Desheng; Kandel, Gabor; Brunetta, Jason; Kim, Connie; Sheth, Prameet M.; Kaul, Rupert; Loutfy, Mona R.

Published Ahead-of-Print

Abstract

Background: Highly active antiretroviral therapy (HAART) dramatically reduces plasma HIV-1 viremia. However, despite completely suppressive HAART, it has been suggested that low-levels of viral replication may persist in the gut mucosa and elsewhere in individuals on long-term HAART.

Objective: We conducted a double-blind randomized, placebo-controlled trial (RCT) evaluating whether intensification of HAART in long-term virologically suppressed individuals with raltegravir is associated with a reduction in the level of proviral HIV-1 DNA in CD4+ T cells in blood and the sigmoid colon (gut).

Methods: Long-term (>4 years) virologically suppressed HIV-infected individuals on standard HAART were randomized 1:1 in a double-blind fashion to receive raltegravir (400mg twice/day) or placebo for 48 weeks. After week 48, all participants were treated with raltegravir to week 96. Blood and sigmoid biopsies were sampled and the frequency of CD4+ T cells carrying HIV-1 proviral DNA was determined.

Results: 24 study patients were recruited. At 48 weeks, no difference was apparent between participants receiving raltegravir or placebo in blood HIV-1 proviral levels (p=0.62), CD4+ T cell counts (p=0.25) and gut proviral loads (p=0.74). Similarly, prolonged raltegravir intensification up to week 96 had no further effect on both blood and gut HIV-1 proviral loads and blood CD4+ T cell counts.

Conclusion: In long-term virologically suppressed patients on standard HAART, intensification with raltegravir did not result in further decay of CD4+ T cells carrying HIV-1 proviral DNA in either the blood or gut after 48 or 96 weeks of therapy, or in any increase in CD4+ T cell counts.

Underestimating the (CD4 T Cell) Help

Following on from the recent post about the importance of virus-specific CD4 T cells in controlling SIV, another new paper adds to the evidence that they also play an important role in HIV infection. Conducted by the laboratory of Hendrik Streeck at the Ragon Institute in collaboration with David Heckerman at Microsoft, the study "represents the first comprehensive analysis conducted at the population level to identify HIV-specific CD4 T cell responses to individual HIV protein subunits and peptides and to elucidate the immunodominance profile of these responses in a large cohort of HIV-controllers and progressors." Given that there has long been an appreciation of the importance of CD4 T cells in immunity against many pathogens, it seems quite remarkable that it has taken until 2011 for such a study to be undertaken. The authors themselves note: "surprisingly little is known about the presence of these responses in the setting of HIV infection."

The main findings include:

• Individuals controlling HIV replication in the absence of treatment have HIV-specific CD4 T cell responses targeting a greater number of peptides on average compared to those with progressive infection (10.9 vs. 6.6).
• The breadth of the HIV-specific CD4 T cell response was inversely correlated with viral load, and this association was driven by CD4 T cells targeting the Gag protein.
• The magnitude of the CD4 T cell response to Gag showed a strong inverse correlation with viral load.
• Responses to Gag were associated with low viral load whereas responses to Env were linked to high viral load, and the ratio between Gag and Env responses was strongly correlated with viral load control: the lowest mean Env/Gag ratio was found in elite controllers (0.20) while the highest mean ratio was in progressors with high viral loads (2.63).
• CD4 T cell responses to three highly conserved Gag epitopes were identified as being strongly predictive of immunological control of HIV replication, independently of host HLA types.

The authors conclude: "Taken together, these data are consistent with our hypothesis that HIV-specific CD4 T cell responses are likely to be beneficial in the control of HIV during chronic infection."

In a separate paper just published online by the Journal of Immunology, Daniel McDermott and Steven Varga report new data on virus-specific CD4 T cells in the context of LCMV infection in mice. The researchers have developed a new method to assess the magnitude of the CD4 T cell response that uses cell surface markers (CD11a and CD49d) as opposed to previously used techniques that rely on measuring responses to specific antigens. By employing this approach, they are able to demonstrate that the CD4 T cell response to LCMV is much larger than prior studies suggested, comprising up to 50% of peripheral blood CD4 T cells in C57BL/6 mice at the peak (versus the 10% estimated previously in the same mouse strain). In the subsequent memory phase of the immune response, approximately 6.5% of CD4 T cells were LCMV-specific, also considerably higher than prior estimates. The researchers note, however, that the genetic background of the mice has a large influence; in the BALB/c mouse strain for example, the peak response was lower at around 15%.

The overall conclusion of the authors is that current methods have significantly underestimated the total magnitude of pathogen-specific CD4 T cell responses; they posit that, in contrast, their new approach can “accurately track the kinetics and magnitude of the entire endogenous CD4 T cell response from the expansion phase into memory.”

JVI Accepts, published online ahead of print on 26 October 2011

J. Virol. doi:10.1128/JVI.05577-11

HIV-specific CD4 T cell responses to different viral proteins have discordant associations with viral load and clinical outcome

Srinika Ranasinghe1, Michael Flanders1, Sam Cutler1, Damien Z. Soghoian1, Musie Ghebremichael1, Isaiah Davis1, Madelene Lindqvist1, Florencia Pereyra1, Bruce D. Walker1,2, David Heckerman3, and Hendrik Streeck1

1 Ragon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

2 Howard Hughes Medical Institute, Chevy Chase, MD, USA

3 Microsoft Research, Redmond, Washington, US

ABSTRACT

A successful prophylactic vaccine is characterized by long-lived immunity, which is critically dependent on CD4 T cell-mediated helper signals. Indeed, most licensed vaccines induce antigen-specific CD4 T cell responses, in addition to high affinity antibodies. However, despite the important role of CD4 T cells in vaccine design and natural infection, few studies have characterized HIV-specific CD4 T cells due to their preferential susceptibility to HIV infection. To establish, on the population level, the impact of HIV-specific CD4 T cells on viral control and define the specificity of HIV-specific CD4 T cell peptide targeting, we conducted a comprehensive analysis of these responses to the entire HIV proteome in 93 subjects at different stages of HIV infection. We show that HIV-specific CD4 T cell responses were detectable in 92% of individuals, and the breadth of these responses showed a significant inverse correlation with viral load (p=0.009, R=-0.31). In particular, CD4 T cell responses targeting Gag were robustly associated with lower viremia (p=0.0002, R=-0.45). Importantly, differences in the immunodominance profile of HIV-specific CD4 T cell responses distinguished HIV controllers from progressors. Furthermore, Gag/Env ratios were a potent marker of viral control; with a high frequency and magnitude of Gag responses and low proportion of Env responses associated with effective immune control. At the epitope-level, targeting of three distinct Gag peptides was linked to spontaneous HIV control (Probability=0.60-0.85). Inclusion of these immunogenic proteins and peptides in future HIV vaccines may act as a critical cornerstone for enhancing protective T cell responses.

The Journal of Immunology

Published online before print October 31, 2011, doi: 10.4049/​jimmunol.1102104

Quantifying Antigen-Specific CD4 T Cells during a Viral Infection: CD4 T Cell Responses Are Larger Than We Think

Daniel S. McDermott* and Steven M. Varga*,†‡

*Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242;

†Department of Pathology, University of Iowa, Iowa City, IA 52242; and

‡Department of Microbiology, University of Iowa, Iowa City, IA 52242

Abstract

The number of virus-specific CD8 T cells increases substantially during an acute infection. Up to 90% of CD8 T cells are virus specific following lymphocytic choriomeningitis virus (LCMV) infection. In contrast, studies identifying virus-specific CD4 T cell epitopes have indicated that CD4 T cells often recognize a broader array of Ags than CD8 T cells, consequently making it difficult to accurately quantify the total magnitude of pathogen-specific CD4 T cell responses. In this study, we show that CD4 T cells become CD11ahiCD49d+ after LCMV infection and retain this expression pattern into memory. During the effector phase, all the LCMV-specific IFN-γ+ CD4 T cells display a CD11ahiCD49d+ cell surface expression phenotype. In addition, only memory CD11ahiCD49d+ CD4 T cells make IFN-γ after stimulation. Furthermore, upon secondary LCMV challenge, only CD11ahiCD49d+ memory CD4 T cells from LCMV-immune mice undergo proliferative expansion, demonstrating that CD11ahiCD49d+ CD4 T cells are truly Ag specific. Using the combination of CD11a and CD49d, we demonstrate that up to 50% of the CD4 T cells are virus specific during the peak of the LCMV response. Our results indicate that the magnitude of the virus-specific CD4 T cell response is much greater than previously recognized.

New Studies on HIV and the Diseases of Aging

The December 1^st issue of Clinical Infectious Diseases contains a raft of papers addressing the issue of HIV and aging (abstracts and links below). A report from the Swiss HIV Cohort Study documents that illnesses typically associated with aging are now the most common causes of morbidity in their cohort, which contains an increasing proportion of individuals aged 50 or older (see graph). In contrast, opportunistic infections make only a minor contribution in the current era of effective antiretroviral therapy (ART). An accompanying editorial by Mike Saag highlights the implications for providing appropriate multidisciplinary care to people with HIV as they age.  

 

Age distribution among active participants of the Swiss HIV Cohort Study over time. Hasse B et al. Clin Infect Dis. 2011;53:1130-1139. © The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.

While there are ongoing debates about whether HIV infection is linked to premature aging—some studies have suggested the risk of aging-associated diseases is increased among HIV-positive people compared to age-matched HIV-negative individuals, while other studies have disputed these findings—the Swiss HIV Cohort Study paper emphasizes that whether or not they are occurring sooner, these morbidities are now the main concern in the long-term care of people with HIV. In discussing their findings, the authors note that the incidence of cancer, heart attacks and diabetes among members of their cohort aged 50-64 was higher than described in studies of somewhat comparable HIV-negative cohorts, but they also stress that "a comparison of our results with an age-matched HIV-uninfected population with similar comorbidity or behavior is difficult, because we had no suitable HIV-uninfected control group in our country."

Giovanni Guaraldi and colleagues from the University of Modena and Reggio Emilia in Italy attempted to address this issue in their study, which compared the occurrence of non-infectious co-morbidities (NICMs) and polypathology (the presence of more than one NICM) among HIV-positive people on ART and a matched HIV-negative control group from the general population (from 2002 through 2009). The NICMs captured in the study included cardiovascular disease, hypertension, diabetes mellitus, bone fractures, and renal failure. The results revealed that prevalence of NICMs and polypathology was higher in HIV-positive individuals across all age categories. The prevalence of polypathology among people with HIV aged 41-50 was similar to the prevalence among HIV-negative controls aged 51-60.

Interpretation of the findings is complicated by the fact that the data from HIV-positive individuals was all derived from a metabolic clinic at Modena. Part of this population is comprised of local people from main HIV clinic at Modena who are automatically referred to the metabolic clinic if they are on ART. However, the population also includes a large proportion of HIV-positive individuals who are referred to the Modena metabolic clinic from neighboring centers due to metabolic issues such as lipodystrophy, and this would appear to account for the unusually high prevalence of this condition among the study cohort (74%). To assess whether this over-representation of people with metabolic issues had biased their results, the study authors compared the incidence of NICMs and polypathology among the local referrals to those from the neighboring centers but—perhaps surprisingly, as Jacqueline Capeau notes in an accompanying editorial commentary—they found no difference.

The authors conclude: "our findings suggest that an aggressive approach to the screening, diagnosis, and treatment of NICMs is warranted as part of routine healthcare for HIV-infected patients. Furthermore, our data suggest that onset of such screening should commence at a substantially earlier age for HIV-infected persons, compared with HIV-uninfected persons, possibly at least a decade in advance. Additional studies are needed to further evaluate the impact of convergent age-related NICMs on age-related functional status, frailty, and disability among ART-experienced HIV-infected persons and to provide insights into accelerated aging processes that may be associated with chronic HIV infection."

The last paper of the raft describes a population-based study carried out in Denmark to assess the risk of cataract surgery among HIV-positive individuals compared to large group of matched HIV-negative controls. Risk was found to be greater among the HIV-positive population, with the highest risk among those with CD4 T cell counts below 200 (either on or off ART). Individuals on ART with CD4 T cell counts over 200 still showed a higher risk than both the general population and HIV-positive people with over 200 CD4 T cells who had not yet started ART; the authors note this could reflect a contribution of drug side effects or receipt of ART could be acting as a marker for having reached a stage of illness requiring treatment (which in turn is associated with an elevated cataract risk). Supporting the latter possibility, no association with specific antiretroviral drugs was found. Although the researchers do not claim that their data represents evidence of accelerated aging in the HIV-positive population, they acknowledge that such a phenomenon “cannot be excluded as a possible part of the explanation.”

Clin Infect Dis. 2011 Oct 13. [Epub ahead of print]

Morbidity and Aging in HIV-Infected Persons: The Swiss HIV Cohort Study.

Hasse B, Ledergerber B, Furrer H, Battegay M, Hirschel B, Cavassini M, Bertisch B, Bernasconi E, Weber R; the Swiss HIV Cohort Study.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich and University of Zurich.

Abstract

Background. Patterns of morbidity and mortality among human immunodeficiency virus (HIV)-infected individuals taking antiretroviral therapy are changing as a result of immune reconstitution and improved survival. We studied the influence of aging on the epidemiology of non-AIDS diseases in the Swiss HIV Cohort Study.

Methods. The Swiss HIV Cohort Study is a prospective observational cohort established in 1988 with continuous enrollment. We determined the incidence of clinical events (per 1000 person-years) from January 2008 (when a new questionnaire on non-AIDS-related morbidity was introduced) through December 2010. Differences across age groups were analyzed using Cox regression, adjusted for CD4 cell count, viral load, sex, injection drug use, smoking, and years of HIV infection.

Results. Overall, 8444 (96%) of 8848 participants contributed data from 40 720 semiannual visits; 2233 individuals (26.4%) were aged 50-64 years, and 450 (5.3%) were aged ≥65 years. The median duration of HIV infection was 15.4 years (95% confidence interval [CI], 9.59-22.0 years); 23.2% had prior clinical AIDS. We observed 994 incident non-AIDS events in the reference period: 201 cases of bacterial pneumonia, 55 myocardial infarctions, 39 strokes, 70 cases of diabetes mellitus, 123 trauma-associated fractures, 37 fractures without adequate trauma, and 115 non-AIDS malignancies. Multivariable hazard ratios for stroke (17.7; CI, 7.06-44.5), myocardial infarction (5.89; 95% CI, 2.17-16.0), diabetes mellitus (3.75; 95% CI, 1.80-7.85), bone fractures without adequate trauma (10.5; 95% CI, 3.58-30.5), osteoporosis (9.13; 95% CI, 4.10-20.3), and non-AIDS-defining malignancies (6.88; 95% CI, 3.89-12.2) were elevated for persons aged ≥65 years.

Conclusions. Comorbidity and multimorbidity because of non-AIDS diseases, particularly diabetes mellitus, cardiovascular disease, non-AIDS-defining malignancies, and osteoporosis, become more important in care of HIV-infected persons and increase with older age.

Clin Infect Dis. 2011 Oct 13. [Epub ahead of print]

EDITORIAL COMMENTARY: HIV Now Firmly Established in the Middle Ages.

Saag MS.

Source

Center for AIDS Research, University of Alabama at Birmingham.

Clin Infect Dis. 2011 Oct 13. [Epub ahead of print]

Premature Age-Related Comorbidities Among HIV-Infected Persons Compared With the General Population.

Guaraldi G, Orlando G, Zona S, Menozzi M, Carli F, Garlassi E, Berti A, Rossi E, Roverato A, Palella F.

Department of Medicine and Medical Specialities, University of Modena and Reggio Emilia.

Abstract

Background. Human immunodeficiency virus (HIV)-infected patients may have a greater risk of noninfectious comorbidities (NICMs) compared with the general population. We assessed the prevalence and risk factors for NICMs in a large cohort of HIV-infected adults and compared these findings with data from matched control subjects.

Methods. We performed a case-control study involving antiretroviral therapy (ART)-experienced HIV-infected patients treated at Modena University, Italy, from 2002 through 2009. These patients were compared with age-, sex-, and race-matched adults (control subjects) from the general population included in the CINECA ARNO database. NICMs included cardiovascular disease, hypertension, diabetes mellitus, bone fractures, and renal failure. Polypathology (Pp) was defined as the concurrent presence of ≥2 NICMs. Logistic regression models were constructed to evaluate associated predictors of NICMs and Pp.

Results. There were 2854 patients and 8562 control subjects. The mean age was 46 years, and 37% were women. Individual NICM and Pp prevalences in each age stratum were higher among patients than among controls (all P <.001). Pp prevalence among patients aged 41-50 years was similar to that among controls aged 51-60 years (P value was not statistically significant); diabetes mellitus, cardiovascular disease, bone fractures, and renal failure were statistically independent after adjustment for sex, age, and hypertension. Logistic regression models showed that independent predictors of Pp in the overall cohort were (all P < .001) age (odds ratio [OR], 1.11), male sex (OR, 1.77), nadir CD4 cell count <200 cells/μL (OR, 4.46), and ART exposure (OR, 1.01).

Conclusions. Specific age-related NICMs and Pp were more common among HIV-infected patients than in the general population. The prevalence of Pp in HIV-infected persons anticipated Pp prevalence observed in the general population among persons who were 10 years older, and HIV-specific cofactors (lower nadir CD4 cell count and more prolonged ART exposure) were identified as risk factors. These data support the need for earlier screening for NICMs in HIV-infected patients.

Clin Infect Dis. 2011 Oct 13. [Epub ahead of print]

EDITORIAL COMMENTARY: Premature Aging and Premature Age-Related Comorbidities in HIV-Infected Patients: Facts and Hypotheses.

Capeau J.

UPMC Univ Paris 06, UMR_S938, Inserm, CDR Saint-Antoine, F-75012 and AP-HP, Hôpital Tenon, F-75020, Paris, France.

Clin Infect Dis. 2011 Oct 13. [Epub ahead of print]

Risk of Cataract Surgery in HIV-Infected Individuals: A Danish Nationwide Population-Based Cohort Study.

Rasmussen LD, Kessel L, Molander LD, Pedersen C, Gerstoft J, Kronborg G, Obel N.

Department of Infectious Diseases, Odense University Hospital.

Abstract

Background. Premature aging has been suggested a risk factor for early death in patients infected with human immunodeficiency virus (HIV). Therefore, the risk of age-related diseases, such as cataracts, should be increased in this population. In a nationwide, population-based cohort study we assessed the risk of cataract surgery in HIV-infected individuals compared with the general population.

Methods. We identified 5315 HIV-infected individuals from a Danish national cohort of HIV-infected individuals and a population-based age- and sex-matched comparison cohort of 53 150 individuals. Data on cataract surgery were obtained from the Danish National Hospital registry. Cumulative incidence curves were constructed. Incidence rate ratios (IRRs) and impact of immunodeficiency, highly active antiretroviral therapy (HAART), and treatment with abacavir, tenofovir, protease inhibitors, and nonnucleoside analogue reverse-transcriptase inhibitors (NNRTIs) were estimated by Poisson regression analyses and adjusted for age, sex, and calendar year.

Results. HIV-infected individuals had a higher risk of cataract surgery than the comparison cohort (adjusted IRR, 1.87; 95% confidence interval (CI): 1.50-2.33). The highest risk was found in patients with a CD4 cell count ≤200 cells/μL (adjusted IRR before HAART initiation, 3.11 [95% CI, 1.26-7.63]; adjusted IRR after HAART initiation, 4.74 [95% CI, 2.60-8.62]). In patients not receiving HAART and those receiving HAART with a CD4 cell count >200 cells/mL the adjusted IRRs were 0.60 (95% CI: 0.22-1.61) and 1.87 (95% CI: 1.46-2.39). Treatment with abacavir, tenofovir, protease inhibitors, or NNRTIs did not increase the risk substantially.

Conclusions. HIV-infected individuals have an increased risk of cataract surgery. The risk is mainly associated with immunodeficiency and HAART, but accelerated aging cannot be excluded as part of the possible explanation.