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1.  HIV Infection and the Risk of Diabetes Mellitus 
AIDS (London, England)  2009;23(10):1227-1234.
Background
The influence of HIV infection on the risk of diabetes is unclear. We determined the association and predictors of prevalent DM in HIV infected and uninfected veterans.
Methods
We determined baseline prevalence and risk factors for diabetes among HIV infected and uninfected veterans in the Veterans Aging Cohort Study. Logistic regression was used to determine the odds of diabetes in HIV infected and uninfected persons.
Results
We studied 3,327 HIV-infected and 3,240 HIV-uninfected subjects. HIV infected subjects were younger, more likely to be black race, male, have HCV coinfection and a lower body mass index (BMI). HIV infected subjects had a lower prevalence of diabetes at baseline (14.9% vs. 21.4%, P<0.0001). After adjustment for known risk factors, HIV infected individuals had a lower risk of diabetes (OR 0.84, 95% CI 0.72-0.97). Increasing age, male gender, minority race, and BMI were associated with an increased risk. The odds ratio for diabetes associated with increasing age, minority race and BMI were greater among HIV infected veterans. HCV coinfection and nucleoside and non-nucleoside reverse transcriptase inhibitor therapy were associated with a higher risk of diabetes in HIV infected veterans.
Conclusion
While HIV infection itself is not associated with increased risk of diabetes, increasing age, HCV coinfection and BMI have a more profound effect upon the risk of diabetes among HIV infected persons. Further, long term ARV treatment also increases risk. Future studies will need to determine whether incidence of DM differs by HIV status.
doi:10.1097/QAD.0b013e32832bd7af
PMCID: PMC2752953  PMID: 19444074
HIV; diabetes; HCV; risk; antiretroviral therapy
2.  Kidney and liver organ transplantation in persons with human immunodeficiency virus 
Executive Summary
Objective
The objective of this analysis is to determine the effectiveness of solid organ transplantation in persons with end stage organ failure (ESOF) and human immunodeficiency virus (HIV+)
Clinical Need: Condition and Target Population
Patients with end stage organ failure who have been unresponsive to other forms of treatment eventually require solid organ transplantation. Similar to persons who are HIV negative (HIV−), persons living with HIV infection (HIV+) are at risk for ESOF from viral (e.g. hepatitis B and C) and non-viral aetiologies (e.g. coronary artery disease, diabetes, hepatocellular carcinoma). Additionally, HIV+ persons also incur risks of ESOF from HIV-associated nephropathy (HIVAN), accelerated liver damage from hepatitis C virus (HCV+), with which an estimated 30% of HIV positive (HIV+) persons are co-infected, and coronary artery disease secondary to antiretroviral therapy. Concerns that the need for post transplant immunosuppression and/or the interaction of immunosuppressive drugs with antiretroviral agents may accelerate the progression of HIV disease, as well as the risk of opportunistic infections post transplantation, have led to uncertainty regarding the overall benefit of transplantation among HIV+ patients. Moreover, the scarcity of donor organs and their use in a population where the clinical benefit of transplantation is uncertain has limited the availability of organ transplantation to persons living with ESOF and HIV.
With the development of highly active anti retroviral therapy (HAART), which has been available in Canada since 1997, there has been improved survival and health-related quality of life for persons living with HIV. HAART can suppress HIV replication, enhance immune function, and slow disease progression. HAART managed persons can now be expected to live longer than those in the pre-HAART era and as a result many will now experience ESOF well before they experience life-threatening conditions related to HIV infection. Given their improved prognosis and the burden of illness they may experience from ESOF, the benefit of solid organ transplantation for HIV+ patients needs to be reassessed.
Evidence-Based Analysis Methods
Research Questions
What are the effectiveness and cost effectiveness of solid organ transplantation in HIV+ persons with ESOF?
Literature Search
A literature search was performed on September 22, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 1996 to September 22, 2009.
Inclusion Criteria
Systematic review with or without a Meta analysis, RCT, Non-RCT with controls
HIV+ population undergoing solid organ transplantation
HIV+ population managed with HAART therapy
Controls include persons undergoing solid organ transplantation who are i) HIV− ii) HCV+ mono-infected, and iii) HIV+ persons with ESOF not transplanted.
Studies that completed and reported results of a Kaplan-Meier Survival Curve analysis.
Studies with a minimum (mean or medium) follow up of 1-year.
English language citations
Exclusion Criteria
Case reports and case series were excluded form this review.
Outcomes of Interest
i) Risk of Death after transplantation
ii) Death censored graft survival (DCGS)
iii) HIV disease progression defined as the post transplant incidence of:
- opportunistic infections or neoplasms,
- CD4+ T-cell count < 200mm3, and
- any detectable level of plasma HIV viral load.
iv) Acute graft rejection,
v) Return to dialysis,
vi) Recurrence of HCV infection
Summary of Findings
No direct evidence comparing an HIV+ cohort undergoing transplantation with the same not undergoing transplantation (wait list) was found in the literature search.
The results of this review are reported for the following comparison cohorts undergoing transplantation:
i) Kidney Transplantation: HIV+ cohort compared with HIV− cohort
ii) Liver Transplantation: HIV+ cohort compared with HIV− negative cohort
iii) Liver Transplantation: HIV+ HCV+ (co-infected) cohort compared with HCV+ (mono-infected) cohort
Kidney Transplantation: HIV+ vs. HIV−
Based on a pooled HIV+ cohort sample size of 285 patients across four studies, the risk of death after kidney transplantation in an HIV+ cohort does not differ to that of an HIV− cohort [hazard ratio (HR): 0.90; 95% CI: 0.36, 2.23]. The quality of evidence supporting this outcome is very low.
Death censored graft survival was reported in one study with an HIV+ cohort sample size of 100, and was statistically significantly different (p=.03) to that in the HIV− cohort (n=36,492). However, the quality of evidence supporting this outcome was determined to be very low. There was also uncertainty in the rate of return to dialysis after kidney transplantation in both the HIV+ and HIV− groups and the effect, if any, this may have on patient survival. Because of the very low quality evidence rating, the effect of kidney transplantation on HIV-disease progression is uncertain.
The rate of acute graft rejection was determined using the data from one study. There was a nonsignificant difference between the HIV+ and HIV− cohorts (OR 0.13; 95% CI: 0.01, 2.64), although again, because of very low quality evidence there is uncertainty in this estimate of effect.
Liver Transplantation: HIV+ vs. HIV−
Based on a combined HIV+ cohort sample size of 198 patient across five studies, the risk of death after liver transplantation in an HIV+ cohort (with at least 50% of the cohort co-infected with HCV+) is statistically significantly 64% greater compared with an HIV− cohort (HR: 1.64; 95% CI: 1.32, 2.02). The quality of evidence supporting this outcome is very low.
Death censored graft survival was reported for an HIV+ cohort in one study (n=11) however the DCGS rate of the contemporaneous control HIV− cohort was not reported. Because of sparse data the quality of evidence supporting this outcome is very low indicating death censored graft survival is uncertain.
Both the CD4+ T-cell count and HIV viral load appear controlled post transplant with an incidence of opportunistic infection of 20.5%. However, the quality of this evidence for these outcomes is very low indicating uncertainty in these effects. Similarly, because of very low quality evidence there is uncertainty in the rate of acute graft rejection among both the HIV+ and HIV− groups
Liver Transplantation: HIV+/HCV+ vs. HCV+
Based on a combined HIV+/HCV+ cohort sample size of 156 from seven studies, the risk of death after liver transplantation is significantly greater (2.8 fold) in a co-infected cohort compared with an HCV+ mono-infected cohort (HR: 2.81; 95% CI: 1.47, 5.37). The quality of evidence supporting this outcome is very low. Death censored graft survival evidence was not available.
Regarding disease progression, based on a combined sample size of 71 persons in the co-infected cohort, the CD4+ T-cell count and HIV viral load appear controlled post transplant; however, again the quality of evidence supporting this outcome is very low. The rate of opportunistic infection in the co-infected cohort was 7.2%. The quality of evidence supporting this estimate is very low, indicating uncertainty in these estimates of effect.
Based on a combined HIV+/HCV+ cohort (n=57) the rate of acute graft rejection does not differ to that of an HCV+ mono-infected cohort (OR: 0.88; 95% CI: 0.44, 1.76). Also based on a combined HIV+/HCV+ cohort (n=83), the rate of HCV+ recurrence does not differ to that of an HCV+ mono-infected cohort (OR: 0.66; 95% CI: 0.27, 1.59). In both cases, the quality of the supporting evidence was very low.
Overall, because of very low quality evidence there is uncertainty in the effect of kidney or liver transplantation in HIV+ persons with end stage organ failure compared with those not infected with HIV. Examining the economics of this issue, the cost of kidney and liver transplants in an HIV+ patient population are, on average, 56K and 147K per case, based on both Canadian and American experiences.
PMCID: PMC3377507  PMID: 23074407
3.  The Risk of Incident Coronary Heart Disease Among Veterans with and without HIV and Hepatitis C 
Background
Whether hepatitis C (HCV) confers additional coronary heart disease (CHD) risk among Human Immunodeficiency Virus (HIV) infected individuals is unclear. Without appropriate adjustment for antiretroviral therapy, CD4 count, and HIV-1 RNA, and substantially different mortality rates among those with and without HIV and HCV infection, the association between HIV, HCV, and CHD may be obscured.
Methods and Results
We analyzed data on 8579 participants (28% HIV+, 9% HIV+HCV+) from the Veterans Aging Cohort Study Virtual Cohort who participated in the 1999 Large Health Study of Veteran Enrollees. We analyzed data collected on HIV and HCV status, risk factors for and the incidence of CHD, and mortality from 1/2000–7/2007. We compared models to assess CHD risk when death was treated as a censoring event and as a competing risk. During the median 7.3 years of follow-up, there were 194 CHD events and 1186 deaths. Compared with HIV−HCV− Veterans, HIV+ HCV+ Veterans had a significantly higher risk of CHD regardless of whether death was adjusted for as a censoring event (adjusted hazard ratio (HR)=2.03, 95% CI=1.28–3.21) or a competing risk (adjusted HR=2.45, 95% CI=1.83–3.27 respectively). Compared with HIV+HCV− Veterans, HIV+ HCV+ Veterans also had a significantly higher adjusted risk of CHD regardless of whether death was treated as a censored event (adjusted HR=1.93, 95% CI=1.02–3.62) or a competing risk (adjusted HR =1.46, 95% CI=1.03–2.07).
Conclusions
HIV+HCV+ Veterans have an increased risk of CHD compared to HIV+HCV−, and HIV−HCV− Veterans.
doi:10.1161/CIRCOUTCOMES.110.957415
PMCID: PMC3159506  PMID: 21712519
viruses; coronary disease; mortality; multi morbidity
4.  Changes in HIV Incidence among People Who Inject Drugs in Taiwan following Introduction of a Harm Reduction Program: A Study of Two Cohorts 
PLoS Medicine  2014;11(4):e1001625.
Kenrad Nelson and colleagues report on the association between HIV incidence and exposure to a national harm-reduction program among people who inject drugs in Taiwan.
Please see later in the article for the Editors' Summary
Background
Harm reduction strategies for combating HIV epidemics among people who inject drugs (PWID) have been implemented in several countries. However, large-scale studies using sensitive measurements of HIV incidence and intervention exposures in defined cohorts are rare. The aim of this study was to determine the association between harm reduction programs and HIV incidence among PWID.
Methods and Findings
The study included two populations. For 3,851 PWID who entered prison between 2004 and 2010 and tested HIV positive upon incarceration, we tested their sera using a BED HIV-1 capture enzyme immunoassay to estimate HIV incidence. Also, we enrolled in a prospective study a cohort of 4,357 individuals who were released from prison via an amnesty on July 16, 2007. We followed them with interviews at intervals of 6–12 mo and by linking several databases. A total of 2,473 participants who were HIV negative in January 2006 had interviews between then and 2010 to evaluate the association between use of harm reduction programs and HIV incidence. We used survival methods with attendance at methadone clinics as a time-varying covariate to measure the association with HIV incidence. We used a Poisson regression model and calculated the HIV incidence rate to evaluate the association between needle/syringe program use and HIV incidence. Among the population of PWID who were imprisoned, the implementation of comprehensive harm reduction programs and a lower mean community HIV viral load were associated with a reduced HIV incidence among PWID. The HIV incidence in this population of PWID decreased from 18.2% in 2005 to 0.3% in 2010. In an individual-level analysis of the amnesty cohort, attendance at methadone clinics was associated with a significantly lower HIV incidence (adjusted hazard ratio: 0.20, 95% CI: 0.06–0.67), and frequent users of needle/syringe program services had lower HIV incidence (0% in high NSP users, 0.5% in non NSP users). In addition, no HIV seroconversions were detected among prison inmates.
Conclusions
Although our data are affected by participation bias, they strongly suggest that comprehensive harm- reduction services and free treatment were associated with reversal of a rapidly emerging epidemic of HIV among PWID.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 35 million people worldwide are currently infected with HIV, the virus that causes AIDS, and about 2.3 million people become newly infected every year. HIV is mainly transmitted through unprotected sex with an infected partner. However, people who inject drugs (PWID) have a particularly high risk of HIV infection because blood transfer through needle and syringe sharing can transmit the virus. It is estimated that 5%–10% of all people living with HIV are PWID. Indeed, in some regions of the world the primary route of HIV transmission is through shared drug injection equipment and the prevalence (the proportion of a population that has a specific disease) of HIV infection among PWID is very high. In Asia, for example, more than a quarter of PWID are HIV positive. Because the high prevalence of HIV among PWID poses a global health challenge, bodies such as the Joint United Nations Programme on HIV/AIDS endorse harm reduction strategies to prevent risky injection behaviors among PWID. These strategies include the provision of clean needles and syringes, opioid substitution therapy such as methadone maintenance treatment, and antiretroviral treatment for HIV-positive PWID.
Why Was This Study Done?
Although harm reduction strategies for combating HIV epidemics among PWID have been implemented in several countries, few large-scale studies have examined the association between HIV incidence (the proportion of new cases of HIV in a population per year) and exposure to harm reduction programs among PWID. In this cohort study (an investigation that determines the characteristics of a group of people and then follows them over time), the researchers determine the association between harm reduction programs and HIV incidence among PWID in Taiwan. HIV infections used to be rare among the 60,000 PWID living in Taiwan, but after the introduction of a new HIV strain into the country in 2003, an HIV epidemic spread rapidly. In response, the Taiwanese government introduced a pilot program of harm reduction that included the provision of clean needles and syringes and health education in July 2005. The program was expanded to include methadone maintenance treatment in early 2006 and implemented nationwide in June 2006.
What Did the Researchers Do and Find?
The researchers enrolled two study populations. The first cohort comprised 3,851 PWID who were incarcerated for illicit drug use between 2004 and 2010 and who tested positive for HIV upon admission into prison. By using the BED assay, which indicates whether an HIV infection is recent, the researchers were able to determine the HIV incidence among the prisoners. In 2004, the estimated HIV incidence among prisoners with a history of drug injection was 6.44%. The incidence peaked in 2005 at 18.2%, but fell to 0.3% in 2010.
The second study population comprised 2,473 individuals who were HIV negative on January 1, 2006, and who had been incarcerated for drug use crimes but were released on July 16, 2007, during an amnesty. The researchers regularly interviewed these participants between their release and 2010 about their use of harm reduction interventions, and obtained other data about them (for example, diagnosis of HIV infection) from official databases. Analysis of all these data indicated that, in this cohort, attendance at methadone maintenance treatment clinics and frequent use of needle and syringe services were both associated with a significantly lower HIV incidence.
What Do These Findings Mean?
These findings suggest that the introduction of a comprehensive harm reduction program in Taiwan was associated with a significant reduction in the HIV incidence rate among PWID. These findings must be interpreted with caution, however. First, because the participants in the study were selected from PWID with histories of incarceration, the findings may not be representative of all PWID in Taiwan or of PWID in other countries. Second, PWID who chose to use needle and syringe services or methadone maintenance treatment clinics might have shared other unknown characteristics that affected their risk of HIV infection. Finally, some of the reduction in HIV incidence seen during the study is likely to be associated with the availability of free treatment, which has been offered to all HIV-positive individuals in Taiwan since 1997. Despite these limitations, these findings suggest that countries with a high prevalence and incidence of HIV among PWID should provide comprehensive harm reduction services to their populations to reduce risky drug injection behaviors.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001625.
Information is available from the US National Institute of Allergy and Infectious diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on injecting drug users and HIV/AIDS and on harm reduction and HIV prevention (in English and Spanish)
The US National Institute on Drug Abuse also provides information about drug abuse and HIV/AIDS (in English and Spanish)
The 2013 UNAIDS World AIDS Day report provides up-to-date information about the AIDS epidemic and efforts to halt it
Personal stories about living with HIV/AIDS are available through Avert, Nam/aidsmap, and Healthtalkonline
doi:10.1371/journal.pmed.1001625
PMCID: PMC3979649  PMID: 24714449
5.  Antiretroviral Therapy for Prevention of Tuberculosis in Adults with HIV: A Systematic Review and Meta-Analysis 
PLoS Medicine  2012;9(7):e1001270.
In a systematic review and meta-analysis, Amitabh Suthar and colleagues investigate the association between antiretroviral therapy and the reduction in the incidence of tuberculosis in adults with HIV infection.
Background
Human immunodeficiency virus (HIV) infection is the strongest risk factor for developing tuberculosis and has fuelled its resurgence, especially in sub-Saharan Africa. In 2010, there were an estimated 1.1 million incident cases of tuberculosis among the 34 million people living with HIV worldwide. Antiretroviral therapy has substantial potential to prevent HIV-associated tuberculosis. We conducted a systematic review of studies that analysed the impact of antiretroviral therapy on the incidence of tuberculosis in adults with HIV infection.
Methods and Findings
PubMed, Embase, African Index Medicus, LILACS, and clinical trial registries were systematically searched. Randomised controlled trials, prospective cohort studies, and retrospective cohort studies were included if they compared tuberculosis incidence by antiretroviral therapy status in HIV-infected adults for a median of over 6 mo in developing countries. For the meta-analyses there were four categories based on CD4 counts at antiretroviral therapy initiation: (1) less than 200 cells/µl, (2) 200 to 350 cells/µl, (3) greater than 350 cells/µl, and (4) any CD4 count.
Eleven studies met the inclusion criteria. Antiretroviral therapy is strongly associated with a reduction in the incidence of tuberculosis in all baseline CD4 count categories: (1) less than 200 cells/µl (hazard ratio [HR] 0.16, 95% confidence interval [CI] 0.07 to 0.36), (2) 200 to 350 cells/µl (HR 0.34, 95% CI 0.19 to 0.60), (3) greater than 350 cells/µl (HR 0.43, 95% CI 0.30 to 0.63), and (4) any CD4 count (HR 0.35, 95% CI 0.28 to 0.44). There was no evidence of hazard ratio modification with respect to baseline CD4 count category (p = 0.20).
Conclusions
Antiretroviral therapy is strongly associated with a reduction in the incidence of tuberculosis across all CD4 count strata. Earlier initiation of antiretroviral therapy may be a key component of global and national strategies to control the HIV-associated tuberculosis syndemic.
Review Registration
International Prospective Register of Systematic Reviews CRD42011001209
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Tuberculosis—a contagious bacterial infection— is a global public-health problem. In 2010, 8.8 million people developed active tuberculosis and 1.4 million people died from the disease. Tuberculosis can be cured by taking powerful antibiotics regularly for several months, and between 1995 and 2010, 46 million people with tuberculosis were successfully treated using DOTS—a directly observed antibiotic regimen designed by the World Health Organization (WHO). Now, though, the HIV epidemic is compromising global tuberculosis control efforts. HIV-positive people are very susceptible to tuberculosis because HIV, the virus that causes AIDS, destroys the immune system cells (including CD4 lymphocytes) that normally combat tuberculosis. In 2010, 1.1 million of the new (incident) cases of tuberculosis were among the 34 million people living with HIV, and 350,000 people died of HIV-associated tuberculosis, making tuberculosis the leading cause of death among HIV-positive people. To tackle HIV-associated tuberculosis, which occurs mainly in developing countries, WHO now recommends that HIV and tuberculosis programs use collaborative approaches such as the Three I's for HIV/TB strategy—intensified tuberculosis case-finding among HIV-positive people, isoniazid preventative therapy for HIV-positive people without active tuberculosis, and (tuberculosis) infection control in healthcare facilities, social settings, and households.
Why Was This Study Done?
Despite progress in scaling up the Three I's for HIV/TB strategy, complementary interventions are still needed to prevent tuberculosis in HIV-positive people. Antiretroviral therapy (ART) lowers the viral load of people infected with HIV and restores their immune system function and could, therefore, prevent HIVassociated tuberculosis, in addition to treating HIV infection. WHO recommends ART for all HIV-positive adults with a CD4 count of less than 350 cells/μl of blood and for all HIVpositive, tuberculosis-positive individuals irrespective of their CD4 count. However, the evidence for ART's preventative impact on tuberculosis has not been systematically examined. Here, the researchers undertake a systematic review (a search that uses predefined criteria to identify all the research on a given topic) and a meta-analysis (a statistical method for combining the results of studies) to investigate the impact of ART initiated at various CD4 counts on the development of tuberculosis in HIV-positive adults in developing countries.
What Did the Researchers Do and Find?
The researchers found 11 studies that compared tuberculosis incidence by ART status in HIV-infected adults over periods longer than six months on average in developing countries and undertook meta-analyses of these studies based on four categories of CD4 count at ART initiation (less than 200 cells/μl, 200–350 cells/μl, greater than 350 cells/μl, and any CD4 count). For all these categories, ART was strongly associated with a reduction in the incidence of tuberculosis. For example, the meta-analysis of the two studies that reported on participants in whom ART was initiated at a CD4 count less than 200 cells/μl yielded a hazard ratio (HR) of 0.16. That is, study participants starting ART when their CD4 count was below 200 cells/μl were about one-sixth as likely to develop tuberculosis as participants not receiving ART. In the metaanalysis of all 11 studies, study participants receiving ART were about one-third as likely to develop tuberculosis as study participants receiving no ART, irrespective of their CD4 count (HR 0.35). Importantly, the CD4 count at which ART was initiated did not significantly alter the magnitude of ART's preventive effect on tuberculosis development.
What Do These Findings Mean?
These findings suggest that ART is strongly associated with a reduction in the incidence of tuberculosis in HIV-positive adults in developing countries, whatever the CD4 count at ART initiation. Because most of the studies in this meta-analysis were observational, these results do not show that ART causes a reduction in tuberculosis incidence—other unknown factors shared by the study participants who received ART may be responsible for their lower tuberculosis incidence. Moreover, factors such as variations in diagnostic methods among the studies included in this meta-analysis may have affected the accuracy of these findings. Nevertheless, the key finding that ART is associated with a significant reduction in tuberculosis cases among adults with CD4 counts greater than 350 cells//μl should be considered by healthcare providers, policymakers, and people living with HIV when weighing the benefits and risks of early ART initiation. It also suggests that early ART initiation (in combination with expanded HIV testing) could be a key component of future global and national strategies to control HIV-associated tuberculosis.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001270.
WHO provides information on all aspects of tuberculosis, including information on tuberculosis and HIV, on the Three I's for HIV/TB, and on ART for tuberculosis prevention (some information is in several languages)
The TB/HIV Working Group is part of the Stop TB Partnership, which is working toward tuberculosis elimination; patient stories about tuberculosis/HIV co-infection are also available on their site
The US Centers for Disease Control and Prevention has information about tuberculosis and about tuberculosis and HIV co-infection
The US National Institute of Allergy and Infectious Diseases also has detailed information on all aspects of tuberculosis including HIV-associated tuberculosis
Information is available from Avert, an international AIDS charity, on HIV-related tuberculosis (in English and Spanish), and from Aidsmap, a non-governmental organization, on HIV-associated tuberculosis
doi:10.1371/journal.pmed.1001270
PMCID: PMC3404110  PMID: 22911011
6.  Do Patterns of Comorbidity Vary by HIV Status, Age, and HIV Severity? 
Patterns of comorbidity among persons with human immunodeficiency virus (HIV) are not well described. We compared comorbidity among veterans with and without HIV infection. The sample consisted of 33,420 HIV-infected veterans and 66,840 HIV-uninfected veterans. We identified and clustered 11 comorbid conditions using validated International Classification of Diseases, 9th Revision, Clinical Modification codes. We defined multimorbidity as the presence of conditions in all clusters. Models restricted to HIV-infected veterans were adjusted for CD4 cell count and viral load. Comorbidity was common (prevalence, 60%–63%), and prevalence varied by HIV status. Differences remained when the veterans were stratified by age. In multivariable analyses, older HIV-infected veterans were more likely to have substance use disorder and multimorbidity. Renal, vascular, and pulmonary diseases were associated with CD4 cell count <200 cells/mm3; hypertension was associated with CD4 cell count >200 cells/mm3. Comorbidity is the rule, and multimorbidity is common among veterans with HIV infection. Patterns of comorbidity differ substantially by HIV status, age, and HIV severity. Primary care guidelines require adaptation for persons with HIV infection.
doi:10.1086/523577
PMCID: PMC3687553  PMID: 18190322
7.  HIV Status, Burden of Comorbid Disease, and Biomarkers of Inflammation, Altered Coagulation, and Monocyte Activation 
We investigated the association between human immunodeficiency virus (HIV) and prevalence of elevated biomarkers of inflammation, altered coagulation, and monocyte activation in a cohort of HIV-infected and uninfected veterans who had a comparable burden of comorbid conditions.
Background. Biomarkers of inflammation, altered coagulation, and monocyte activation are associated with mortality and cardiovascular disease (CVD) in the general population and among human immunodeficiency virus (HIV)–infected people. We compared biomarkers for inflammation, altered coagulation, and monocyte activation between HIV-infected and uninfected people in the Veterans Aging Cohort Study (VACS).
Methods. Biomarkers of inflammation (interleukin-6 [IL-6]), altered coagulation (d-dimer), and monocyte activation (soluble CD14 [sCD14]) were measured in blood samples from 1525 HIV-infected and 843 uninfected VACS participants. Logistic regression was used to determine the association between HIV infection and prevalence of elevated (>75th percentile) biomarkers, adjusting for confounding comorbidities.
Results. HIV-infected veterans had less prevalent CVD, hypertension, diabetes, obesity, hazardous drinking, and renal disease, but more dyslipidemia, hepatitis C, and current smoking than uninfected veterans. Compared to uninfected veterans, HIV-infected veterans with HIV-1 RNA ≥500 copies/mL or CD4 count <200 cells/µL had a significantly higher prevalence of elevated IL-6 (odds ratio [OR], 1.54; 95% confidence interval [CI],1.14–2.09; OR, 2.25; 95% CI, 1.60–3.16, respectively) and d-dimer (OR, 1.97; 95% CI, 1.44–2.71, OR, 1.68; 95% CI, 1.22–2.32, respectively) after adjusting for comorbidities. HIV-infected veterans with a CD4 cell count <200 cells/µL had significantly higher prevalence of elevated sCD14 compared to uninfected veterans (OR, 2.60; 95% CI, 1.64–4.14). These associations still persisted after restricting the analysis to veterans without known confounding comorbid conditions.
Conclusions. These data suggest that ongoing HIV replication and immune depletion significantly contribute to increased prevalence of elevated biomarkers of inflammation, altered coagulation, and monocyte activation. This contribution is independent of and in addition to the substantial contribution from comorbid conditions.
doi:10.1093/cid/cis406
PMCID: PMC3493182  PMID: 22534147
8.  Bacterial Vaginosis Associated with Increased Risk of Female-to-Male HIV-1 Transmission: A Prospective Cohort Analysis among African Couples 
PLoS Medicine  2012;9(6):e1001251.
In a prospective study, Craig Cohen and colleagues investigate the association between bacterial vaginosis and the risk of female-to-male HIV-1 transmission.
Background
Bacterial vaginosis (BV), a disruption of the normal vaginal flora, has been associated with a 60% increased risk of HIV-1 acquisition in women and higher concentration of HIV-1 RNA in the genital tract of HIV-1–infected women. However, whether BV, which is present in up to half of African HIV-1–infected women, is associated with an increase in HIV-1 transmission to male partners has not been assessed in previous studies.
Methods and Findings
We assessed the association between BV on female-to-male HIV-1 transmission risk in a prospective study of 2,236 HIV-1–seropositive women and their HIV-1 uninfected male partners from seven African countries from a randomized placebo-controlled trial that enrolled heterosexual African adults who were seropositive for both HIV-1 and herpes simplex virus (HSV)-2, and their HIV-1–seronegative partners. Participants were followed for up to 24 months; every three months, vaginal swabs were obtained from female partners for Gram stain and male partners were tested for HIV-1. BV and normal vaginal flora were defined as a Nugent score of 7–10 and 0–3, respectively. To reduce misclassification, HIV-1 sequence analysis of viruses from seroconverters and their partners was performed to determine linkage of HIV-1 transmissions. Overall, 50 incident HIV-1 infections occurred in men in which the HIV-1–infected female partner had an evaluable vaginal Gram stain. HIV-1 incidence in men whose HIV-1–infected female partners had BV was 2.91 versus 0.76 per 100 person-years in men whose female partners had normal vaginal flora (hazard ratio 3.62, 95% CI 1.74–7.52). After controlling for sociodemographic factors, sexual behavior, male circumcision, sexually transmitted infections, pregnancy, and plasma HIV-1 RNA levels in female partners, BV was associated with a greater than 3-fold increased risk of female-to-male HIV-1 transmission (adjusted hazard ratio 3.17, 95% CI 1.37–7.33).
Conclusions
This study identified an association between BV and increased risk of HIV-1 transmission to male partners. Several limitations may affect the generalizability of our results including: all participants underwent couples HIV counseling and testing and enrolled in an HIV-1 prevention trial, and index participants had a baseline CD4 count ≥250 cells/mm3 and were HSV-2 seropositive. Given the high prevalence of BV and the association of BV with increased risk of both female HIV-1 acquisition and transmission found in our study, if this association proves to be causal, BV could be responsible for a substantial proportion of new HIV-1 infections in Africa. Normalization of vaginal flora in HIV-1–infected women could mitigate female-to-male HIV-1 transmission.
Trial Registration: ClinicalTrials.com NCT00194519
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Since the first reported case of AIDS in 1981, the number of people infected with HIV, the virus that causes AIDS, has risen steadily. By the end of 2010, 34 million people were living with HIV/AIDS. At the beginning of the epidemic more men than women were infected with HIV. Now, however, 50% of all adults infected with HIV are women and in sub-Saharan Africa, where two-thirds of HIV-positive people live, women account for 59% of people living with HIV. Moreover, among 15–24 year-olds, women are eight times more likely than men to be HIV-positive. This pattern of infection has developed because most people in sub-Saharan Africa contract HIV through unprotected heterosexual sex. The risk of HIV transmission for both men and women in Africa and elsewhere can be reduced by abstaining from sex, by only having one or a few partners, by always using condoms, and by male circumcision. In addition, several studies suggest that antiretroviral therapy (ART) greatly reduces HIV transmission.
Why Was This Study Done?
Unfortunately, in sub-Saharan Africa, only about a fifth of HIV-positive people are currently receiving ART, which means that there is an urgent need to find other effective ways to reduce HIV transmission in this region. In this prospective cohort study (a type of study that follows a group of people for some time to see which personal characteristics are associated with disease development), the researchers investigate whether bacterial vaginosis—a condition in which harmful bacteria disrupt the normal vaginal flora—increases the risk of female-to-male HIV transmission among African couples. Bacterial vaginosis, which is extremely common in sub-Saharan Africa, has been associated with an increased risk of HIV acquisition in women and induces viral replication and shedding in the vagina in HIV-positive women, which may mean that HIV-positive women with bacterial vaginosis are more likely to transmit HIV to their male partners than women without this condition. If this is the case, then interventions that reduce the incidence of bacterial vaginosis might be valuable HIV prevention strategies.
What Did the Researchers Do and Find?
The researchers analyzed data collected from 2,236 heterosexual African couples enrolled in a clinical trial (the Partners in Prevention HSV/HIV Transmission Study) whose primary aim was to investigate whether suppression of herpes simplex virus infection could prevent HIV transmission. In all the couples, the woman was HIV-positive and the man was initially HIV-negative. The female partners were examined every three months for the presence of bacterial vaginosis and the male partners were tested regularly for HIV infection. The researchers also determined whether the men who became HIV-positive were infected with the same HIV strain as their partner to check that their infection had been acquired from this partner. The HIV incidence in men whose partners had bacterial vaginosis was 2.9 per 100 person-years (that is, 2.9 out of every 100 men became HIV-positive per year) whereas the HIV incidence in men whose partners had a normal vaginal flora was 0.76 per 100 person-years. After controlling for factors that might affect the risk of HIV transmission such as male circumcision and viral levels in female partner's blood, the researchers estimated that bacterial vaginosis was associated with a 3.17-fold increased risk of female-to-male HIV transmission in their study population.
What Do These Findings Mean?
These findings suggest that HIV-positive African women with bacterial vaginosis are more than three times as likely to transmit HIV to their male partners as those with a normal vaginal flora. It is possible that some unknown characteristic of the men in this study might have increased both their own risk of HIV infection and their partner's risk of bacterial vaginosis. Nevertheless, because bacterial vaginosis is so common in Africa (half of the women in this study had bacterial vaginosis at least once during follow-up) and because this condition is associated with both female HIV acquisition and transmission, these findings suggest that bacterial vaginosis could be responsible for a substantial proportion of new HIV infections in Africa. Normalization of vaginal flora in HIV-infected women by frequent presumptive treatment with antimicrobials (treatment with a curative dose of antibiotics without testing for bacterial vaginosis) or possibly by treatment with probiotics (live “good” bacteria) might, therefore, reduce female-to-male HIV transmission in sub-Saharan Africa.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001251.
Information is available from the US National Institute of Allergy and infectious diseases on all aspects of HIV infection and AIDS and on bacterial vaginosis
The US Centers for Disease Control and Prevention has information on all aspects of HIV/AIDS, including specific information about HIV/AIDS and women; it also has information on bacterial vaginosis (in English and Spanish)
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment, and information on bacterial vaginosis and HIV transmission (in several languages)
Information is available from Avert, an international AIDS nonprofit group on many aspects of HIV/AIDS, including detailed information on HIV and AIDS prevention, on women, HIV and AIDS and on HIV/AIDS in Africa (in English and Spanish); personal stories of women living with HIV are available; the website Healthtalkonline also provides personal stories about living with HIV
More information about the Partners in Prevention HSV/HIV Transmission Study is available
doi:10.1371/journal.pmed.1001251
PMCID: PMC3383741  PMID: 22745608
9.  Use of lipid lowering agents in rheumatoid arthritis: a population based cohort study 
The Journal of rheumatology  2013;40(7):1082-1088.
Objective
Rheumatoid arthritis (RA) is associated with an increased risk of cardiovascular disease and mortality. Lipid-lowering therapy is reportedly underused in patients with RA. However, longitudinal cohort studies comparing the use of lipid-lowering medications in patients with RA vs the general population are lacking.
Methods
Cardiovascular risk factors, lipid measures and use of lipid-lowering agents were assessed in a population-based inception cohort of patients with RA and a cohort of non-RA subjects followed from 1/1/1988 to 12/31/2008. The National Cholesterol Education Program (NCEP) adult treatment panel III (ATP III) guidelines were assessed at the time of each lipid measure throughout follow-up. Time from meeting guidelines to initiation of lipid-lowering agents was assessed using Kaplan-Meier methods.
Results
The study population included 412 RA and 438 non-RA patients with ≥1 lipid measure during follow-up and no prior use of lipid lowering agents. Rates of lipid testing were lower among patients with RA compared to non-RA subjects. Among patients who met NCEP ATP III criteria for lipid-lowering therapy (n=106 RA and n=120 non-RA), only 27% of RA and 26% of non-RA subjects initiated lipid-lowering agents within 2 years of meeting guidelines for initiation.
Conclusions
There was substantial undertreatment in both the RA and non-RA cohorts who met NCEP ATP III criteria for initiation of lipid-lowering agents. Patients with RA did not have as frequent lipid testing as individuals in the general population.
doi:10.3899/jrheum.121302
PMCID: PMC3891914  PMID: 23637326
rheumatoid arthritis; lipids; lipid lowering therapy
10.  Risk of Heart Failure With Human Immunodeficiency Virus in the Absence of Prior Diagnosis of Coronary Heart Disease 
Archives of internal medicine  2011;171(8):737-743.
Background
Whether human immunodeficiency virus (HIV) infection is a risk factor for heart failure (HF) is not clear. The presence of coronary heart disease and alcohol consumption in this population may confound this association.
Methods
To determine whether HIV infection is a risk factor for incident HF, we conducted a population-based, retrospective cohort study of HIV-infected and HIV-uninfected veterans enrolled in the Veterans Aging Cohort Study Virtual Cohort (VACS-VC) and the 1999 Large Health Study of Veteran Enrollees (LHS) from January 1, 2000, to July 31, 2007.
Results
There were 8486 participants (28.2% HIV-infected) enrolled in the VACS-VC who also participated in the 1999 LHS. During the median 7.3 years of follow-up, 286 incident HF events occurred. Age- and race/ethnicity–adjusted HF rates among HIV-infected and HIV-uninfected veterans were 7.12 (95% confidence interval [CI],6.90-7.34) and 4.82 (95% CI, 4.72-4.91) per 1000 person-years, respectively. Compared with HIV-uninfected veterans, those who were HIV infected had an increased risk ofHF (adjusted hazard ratio [HR], 1.81; 95% CI, 1.39-2.36). This association persisted among veterans who did not have a coronary heart disease event or a diagnosis related to alcohol abuse or dependence before the incident HF event (adjusted HR, 1.96; 95% CI, 1.29-2.98). Compared with HIV-uninfected veterans, those who were HIV infected with a baseline Human immunodeficiency virus 1 (HIV-1) RNA level of 500 or more copies/mL had a higher risk of HF (adjusted HR, 2.28; 95% CI, 1.57-3.32), while those with baseline and a recent HIV-1 RNA level less than 500 copies/mL did not (adjusted HR, 1.10; 95% CI, 0.64-1.89; P< .001 for comparison between high and low HIV-1 RNA groups).
Conclusions
Our data suggest that HIV infection is a risk factor for HF. Ongoing viral replication is associated with a higher risk of developing HF.
doi:10.1001/archinternmed.2011.151
PMCID: PMC3687533  PMID: 21518940
11.  HIV Infection and Risk for Incident Pulmonary Diseases in the Combination Antiretroviral Therapy Era 
Rationale: In aging HIV-infected populations comorbid diseases are important determinants of morbidity and mortality. Pulmonary diseases have not been systematically assessed in the combination antiretroviral therapy (ART) era.
Objectives: To determine the incidence of pulmonary diseases in HIV-infected persons compared with HIV-uninfected persons.
Methods: We analyzed data from the Veterans Aging Cohort Study Virtual Cohort, consisting of 33,420 HIV-infected veterans and 66,840 age, sex, race and ethnicity, and site-matched HIV-uninfected veterans. Using Poisson regression, incidence rates and adjusted incidence rate ratios were calculated to determine the association of HIV with pulmonary disease. The Virtual Cohort was merged with the 1999 Veterans Large Health Survey to adjust for self-reported smoking in a nested sample (14%).
Measurements and Main Results: Incident chronic obstructive pulmonary disease, lung cancer, pulmonary hypertension, and pulmonary fibrosis, as well as pulmonary infections, were significantly more likely among HIV-infected patients compared with uninfected patients in adjusted analyses, although rates of asthma did not differ by HIV status. Bacterial pneumonia and chronic obstructive pulmonary disease were the two most common incident pulmonary diseases, whereas opportunistic pneumonias were less common. Absolute rates of most pulmonary diseases increased with age, although the relative differences between those with and without HIV infection were greatest in younger persons. Chronic obstructive pulmonary disease and asthma, as well as pulmonary infections, were less likely in those with lower HIV RNA levels and use of ART at baseline.
Conclusions: Pulmonary diseases among HIV-infected patients receiving care within the Veterans Affairs Healthcare System in the combination ART era reflect a substantial burden of non–AIDS-defining and chronic conditions, many of which are associated with aging.
doi:10.1164/rccm.201006-0836OC
PMCID: PMC3266024  PMID: 20851926
HIV; respiratory tract diseases; lung diseases, obstructive; pneumonia; pneumonia, bacterial
12.  Measuring Coverage in MNCH: Population HIV-Free Survival among Children under Two Years of Age in Four African Countries 
PLoS Medicine  2013;10(5):e1001424.
Background
Population-based evaluations of programs for prevention of mother-to-child HIV transmission (PMTCT) are scarce. We measured PMTCT service coverage, regimen use, and HIV-free survival among children ≤24 mo of age in Cameroon, Côte D'Ivoire, South Africa, and Zambia.
Methods and Findings
We randomly sampled households in 26 communities and offered participation if a child had been born to a woman living there during the prior 24 mo. We tested consenting mothers with rapid HIV antibody tests and tested the children of seropositive mothers with HIV DNA PCR or rapid antibody tests. Our primary outcome was 24-mo HIV-free survival, estimated with survival analysis. In an individual-level analysis, we evaluated the effectiveness of various PMTCT regimens. In a community-level analysis, we evaluated the relationship between HIV-free survival and community PMTCT coverage (the proportion of HIV-exposed infants in each community that received any PMTCT intervention during gestation or breastfeeding). We also compared our community coverage results to those of a contemporaneous study conducted in the facilities serving each sampled community. Of 7,985 surveyed children under 2 y of age, 1,014 (12.7%) were HIV-exposed. Of these, 110 (10.9%) were HIV-infected, 851 (83.9%) were HIV-uninfected, and 53 (5.2%) were dead. HIV-free survival at 24 mo of age among all HIV-exposed children was 79.7% (95% CI: 76.4, 82.6) overall, with the following country-level estimates: Cameroon (72.6%; 95% CI: 62.3, 80.5), South Africa (77.7%; 95% CI: 72.5, 82.1), Zambia (83.1%; 95% CI: 78.4, 86.8), and Côte D'Ivoire (84.4%; 95% CI: 70.0, 92.2). In adjusted analyses, the risk of death or HIV infection was non-significantly lower in children whose mothers received a more complex regimen of either two or three antiretroviral drugs compared to those receiving no prophylaxis (adjusted hazard ratio: 0.60; 95% CI: 0.34, 1.06). Risk of death was not different for children whose mothers received a more complex regimen compared to those given single-dose nevirapine (adjusted hazard ratio: 0.88; 95% CI: 0.45, 1.72). Community PMTCT coverage was highest in Cameroon, where 75 of 114 HIV-exposed infants met criteria for coverage (66%; 95% CI: 56, 74), followed by Zambia (219 of 444, 49%; 95% CI: 45, 54), then South Africa (152 of 365, 42%; 95% CI: 37, 47), and then Côte D'Ivoire (3 of 53, 5.7%; 95% CI: 1.2, 16). In a cluster-level analysis, community PMTCT coverage was highly correlated with facility PMTCT coverage (Pearson's r = 0.85), and moderately correlated with 24-mo HIV-free survival (Pearson's r = 0.29). In 14 of 16 instances where both the facility and community samples were large enough for comparison, the facility-based coverage measure exceeded that observed in the community.
Conclusions
HIV-free survival can be estimated with community surveys and should be incorporated into ongoing country monitoring. Facility-based coverage measures correlate with those derived from community sampling, but may overestimate population coverage. The more complex regimens recommended by the World Health Organization seem to have measurable public health benefit at the population level, but power was limited and additional field validation is needed.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
For a pregnant woman who is HIV-positive, the discrepancy across the world in outlook for mother and child is stark. Mother-to-child transmission of HIV during pregnancy is now less than 1% in many high-income settings, but occurs much more often in low-income countries. Three interventions have a major impact on transmission of HIV to the baby: antiretroviral drugs, mode of delivery, and type of infant feeding. The latter two are complex, as the interventions commonly used in high-income countries (cesarean section if the maternal viral load is high; exclusive formula feeding) have their own risks in low-income settings. Minimizing the risks of transmitting HIV through effective drug regimes therefore becomes particularly important. Monitoring progress on reducing the incidence of mother-to-child HIV transmission is essential, but not always easy to achieve.
Why Was This Study Done?
A research group led by Stringer and colleagues recently reported a study from four countries in Africa: Cameroon, Côte D'Ivoire, South Africa, and Zambia. The study showed that even in the health facility setting (e.g., hospitals and clinics), only half of infants whose mothers were HIV-positive received the minimum recommended drug treatment (one dose of nevirapine during labor) to prevent HIV transmission. Across the population of these countries, it is possible that fewer receive antiretroviral drugs, as the study did not include women who did not access health facilities. Therefore, the next stage of the study by this research group, reported here, involved going into the communities around these health facilities to find out how many infants under two years old had been exposed to HIV, whether they had received drugs to prevent transmission, and what proportion were alive and not infected with HIV at two years old.
What Did the Researchers Do and Find?
The researchers tested all consenting women who had delivered a baby in the last two years in the surrounding communities. If the mother was found to be HIV-positive, then the infant was also tested for HIV. The researchers then calculated how many of the infants would be alive at two years and free of HIV infection.
Most mothers (78%) agreed to testing for themselves and their infants. There were 7,985 children under two years of age in this study, of whom 13% had been born to an HIV-positive mother. Less than half (46%) of the HIV-positive mothers had received any drugs to prevent HIV transmission. Of the children with HIV-positive mothers, 11% were HIV-infected, 84% were not infected with HIV, and 5% had died. Overall, the researchers estimated that around 80% of these children would be alive at two years without HIV infection. This proportion differed non-significantly between the four countries (ranging from 73% to 84%). The researchers found higher rates of infant survival than they had expected and knew that they might have missed some infant deaths (e.g., if households with infant deaths were less likely to take part in the study).
The researchers found that their estimates of the proportion of HIV-positive mothers who received drugs to prevent transmission were fairly similar between their previous study, looking at health facilities, and this study of the surrounding communities. However, in 14 out of 16 comparisons, the estimate from the community was lower than that from the facility.
What Do These Findings Mean?
This study shows that it would be possible to estimate how many infants are surviving free of HIV infection using a study based in the community, and that these estimates may be more accurate than those for studies based in health facilities. There are still a large proportion of HIV-positive mothers who are not receiving drugs to prevent transmission to the baby. The authors suggest that using two or three drugs to prevent HIV may help to reduce transmission.
There are already community surveys conducted in many low-income countries, but they have not included routine infant testing for HIV. It is now essential that organizations providing drugs, money, and infrastructure in this field consider more accurate means of monitoring incidence of HIV transmission from mother to infant, particularly at the community level.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001424.
The World Health Organization has more information on mother-to-child transmission of HIV
The United Nations Children's Fund has more information on the status of national PMTCT responses in the most affected countries
doi:10.1371/journal.pmed.1001424
PMCID: PMC3646218  PMID: 23667341
13.  Impaired Hepatitis C Virus-Specific T Cell Responses and Recurrent Hepatitis C Virus in HIV Coinfection 
PLoS Medicine  2006;3(12):e492.
Background
Hepatitis C virus (HCV)-specific T cell responses are critical for spontaneous resolution of HCV viremia. Here we examined the effect of a lymphotropic virus, HIV-1, on the ability of coinfected patients to maintain spontaneous control of HCV infection.
Methods and Findings
We measured T cell responsiveness by lymphoproliferation and interferon-γ ELISPOT in a large cohort of HCV-infected individuals with and without HIV infection. Among 47 HCV/HIV-1-coinfected individuals, spontaneous control of HCV was associated with more frequent HCV-specific lymphoproliferative (LP) responses (35%) compared to coinfected persons who exhibited chronic HCV viremia (7%, p = 0.016), but less frequent compared to HCV controllers who were not HIV infected (86%, p = 0.003). Preservation of HCV-specific LP responses in coinfected individuals was associated with a higher nadir CD4 count (r2 = 0.45, p < 0.001) and the presence and magnitude of the HCV-specific CD8+ T cell interferon-γ response (p = 0.0014). During long-term follow-up, recurrence of HCV viremia occurred in six of 25 coinfected individuals with prior control of HCV, but in 0 of 16 HIV-1-negative HCV controllers (p = 0.03, log rank test). In these six individuals with recurrent HCV viremia, the magnitude of HCV viremia following recurrence inversely correlated with the CD4 count at time of breakthrough (r = −0.94, p = 0.017).
Conclusions
These results indicate that HIV infection impairs the immune response to HCV—including in persons who have cleared HCV infection—and that HIV-1-infected individuals with spontaneous control of HCV remain at significant risk for a second episode of HCV viremia. These findings highlight the need for repeat viral RNA testing of apparent controllers of HCV infection in the setting of HIV-1 coinfection and provide a possible explanation for the higher rate of HCV persistence observed in this population.
HIV infection impairs the immune response to HCV. Even individuals who have cleared HCV infection remain at significant risk for a second episode of HCV viremia.
Editors' Summary
Background.
Because of shared transmission routes (contaminated needles, contaminated blood products, and, to a lesser extent, unprotected sex), a large proportion of HIV-infected individuals (estimates range between 25% and 33%) are also infected with the hepatitis C virus (HCV). In most but not all individuals infected with HCV, the virus infection is chronic and causes liver disease that can eventually lead to liver failure. Disease progress is slow; it often takes decades until infected individuals develop serious liver disease. In people infected with both HCV and HIV, however, liver disease caused by HCV often appears sooner and progresses faster. As highly active antiretroviral therapy (HAART) and prophylaxis of opportunistic infections increase the life span of persons living with HIV, HCV-related liver disease has become a major cause of hospital admissions and deaths among HIV-infected persons.
Why Was This Study Done?
A sizable minority of people who are infected with HCV manage to control the virus and never get liver disease, and scientists have found that these people somehow mounted a strong immune response against the hepatitis C virus. CD4+ T cells, the very immune cells that are infected and destroyed by HIV, play an important role in this immune response. The goal of the present study was to better understand how infection with HIV compromises the specific immune response to HCV and thereby the control of HCV disease progression.
What Did the Researchers Do and Find?
The researchers recruited four groups of patients, 94 in total, all of whom were infected with HCV. Two groups comprised patients who were infected with HIV as well as HCV, with either high or undetectable levels of HCV (30 patients in each group). The two other groups included patients not infected with HIV, either with high or undetectable levels of HCV (17 patients in each group). The researchers focused on the individuals who, despite coinfection with HIV, were able to control their HCV infection. They found that those individuals managed to maintain relatively high levels of CD4+ T cells that specifically recognize HCV. However, a quarter of these patients (six out of 25) failed to keep HCV levels down for the entire observation period of up to 2.5 years; their blood levels of HCV rose substantially, most likely due to recurrence of the previously suppressed virus (the researchers could not be certain that none of the patients had become infected again after a new exposure to HCV-contaminated blood, but there was no evidence that they had engaged in risky behavior). The rise of HCV levels in the blood of the relapsed patients coincided with a drop in overall CD4+ T cell numbers. Following relapse in these individuals, HCV did not return to undetectable levels during the study. During the same period none of the 16 HIV-uninfected people with controlled HCV infection experienced a recurrence of detectable HCV.
What Do These Findings Mean?
Despite the relatively small numbers of patients, these results suggest that recurrence of HCV after initial control of the virus is more likely in people who are coinfected with HIV, and that HCV control is lost when CD4+ T cell counts fall. This is one more reason to test all HIV-positive patients for HCV coinfection. Coinfected patients, even those who seem to be controlling HCV and would not automatically receive HCV treatment, should be regularly tested for a rise of HCV levels. In addition, maintaining CD4+ T cells at a high level might be particularly important for those patients, which means that doctors might consider starting HAART therapy earlier than is generally recommended for HIV-infected individuals. Additional studies are needed to support these recommendations, however, especially as this study did not follow the patients long enough to determine the consequences of the observed loss of control of HCV.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030492.
AIDS Treatment Data Network factsheet on HIV/HCV coinfection
US CDC factsheet on HIV/HCV coinfection
American Liver Foundation, information on HIV and HCV
MedlinePlus pages on HCV
doi:10.1371/journal.pmed.0030492
PMCID: PMC1705826  PMID: 17194190
14.  Incident HIV during Pregnancy and Postpartum and Risk of Mother-to-Child HIV Transmission: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(2):e1001608.
Alison Drake and colleagues conduct a systematic review and meta-analysis to estimate maternal HIV incidence during pregnancy and the postpartum period and to compare mother-to-child HIV transmission risk among women with incident versus chronic infection.
Please see later in the article for the Editors' Summary
Background
Women may have persistent risk of HIV acquisition during pregnancy and postpartum. Estimating risk of HIV during these periods is important to inform optimal prevention approaches. We performed a systematic review and meta-analysis to estimate maternal HIV incidence during pregnancy/postpartum and to compare mother-to-child HIV transmission (MTCT) risk among women with incident versus chronic infection.
Methods and Findings
We searched PubMed, Embase, and AIDS-related conference abstracts between January 1, 1980, and October 31, 2013, for articles and abstracts describing HIV acquisition during pregnancy/postpartum. The inclusion criterion was studies with data on recent HIV during pregnancy/postpartum. Random effects models were constructed to pool HIV incidence rates, cumulative HIV incidence, hazard ratios (HRs), or odds ratios (ORs) summarizing the association between pregnancy/postpartum status and HIV incidence, and MTCT risk and rates. Overall, 1,176 studies met the search criteria, of which 78 met the inclusion criterion, and 47 contributed data. Using data from 19 cohorts representing 22,803 total person-years, the pooled HIV incidence rate during pregnancy/postpartum was 3.8/100 person-years (95% CI 3.0–4.6): 4.7/100 person-years during pregnancy and 2.9/100 person-years postpartum (p = 0.18). Pooled cumulative HIV incidence was significantly higher in African than non-African countries (3.6% versus 0.3%, respectively; p<0.001). Risk of HIV was not significantly higher among pregnant (HR 1.3, 95% CI 0.5–2.1) or postpartum women (HR 1.1, 95% CI 0.6–1.6) than among non-pregnant/non-postpartum women in five studies with available data. In African cohorts, MTCT risk was significantly higher among women with incident versus chronic HIV infection in the postpartum period (OR 2.9, 95% CI 2.2–3.9) or in pregnancy/postpartum periods combined (OR 2.3, 95% CI 1.2–4.4). However, the small number of studies limited power to detect associations and sources of heterogeneity.
Conclusions
Pregnancy and the postpartum period are times of persistent HIV risk, at rates similar to “high risk” cohorts. MTCT risk was elevated among women with incident infections. Detection and prevention of incident HIV in pregnancy/postpartum should be prioritized, and is critical to decrease MTCT.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, about 3.4 million children younger than 15 years old (mostly living in sub-Saharan Africa) are infected with HIV, the virus that causes AIDS by gradually destroying immune system cells, thereby leaving infected individuals susceptible to other serious infections. In 2012 alone, 230,000 children (more than 700 every day) were newly infected with HIV. Most HIV infections among children are the result of mother-to-child HIV transmission (MTCT) during pregnancy, delivery, or breastfeeding. The rate of MTCT (and deaths among HIV-positive pregnant women from complications related to HIV infection) can be greatly reduced by testing women for HIV infection during pregnancy (antenatal HIV testing), treating HIV-positive women with antiretroviral drugs (ARVs, powerful drugs that control HIV replication and allow the immune system to recover) during pregnancy, delivery, and breastfeeding, and giving ARVs to their newborn babies.
Why Was This Study Done?
The World Health Organization and the Joint United Nations Programme on HIV/AIDS (UNAIDS) have developed a global plan that aims to move towards eliminating new HIV infections among children by 2015 and towards keeping their mothers alive. To ensure the plan's success, the incidence of HIV (the number of new infections) among women and the rate of MTCT must be reduced by increasing ARV uptake by mothers and their infants for the prevention of MTCT. However, the risk of HIV infection among pregnant women and among women who have recently given birth (postpartum women) is poorly understood because, although guidelines recommend repeat HIV testing during late pregnancy or at delivery in settings where HIV infection is common, pregnant women are often tested only once for HIV infection. The lack of retesting represents a missed opportunity to identify pregnant and postpartum women who have recently acquired HIV and to prevent MTCT by initiating ARV therapy. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic) and meta-analysis (a study that uses statistical methods to combine the results of several studies), the researchers estimate maternal HIV incidence during pregnancy and the postpartum period, and compare the risk of MTCT among women with incident (new) and chronic (long-standing) HIV infection.
What Did the Researchers Do and Find?
The researchers identified 47 studies (35 undertaken in Africa) that examined recent HIV acquisition by women during pregnancy and the 12-month postpartum period. They used random effects statistical models to estimate the pooled HIV incidence rate and cumulative HIV incidence (the number of new infections per number of people at risk), and the association between pregnancy/postpartum status and HIV incidence and MTCT risk and rates. The pooled HIV incidence rate among pregnant/postpartum women estimated from 19 studies (all from sub-Saharan Africa) that reported HIV incidence rates was 3.8/100 person-years. The pooled cumulative HIV incidence was significantly higher in African countries than in non-African countries (3.6% and 0.3%, respectively; a “significant” difference is one that is unlikely to arise by chance). In the five studies that provided suitable data, the risk of HIV acquisition was similar in pregnant, postpartum, and non-pregnant/non-postpartum women. Finally, among African women, the risk of MTCT was 2.9-fold higher during the postpartum period among those who had recently acquired HIV than among those with chronic HIV infection, and 2.3-fold higher during the pregnancy/postpartum periods combined.
What Do These Findings Mean?
These results suggest that women living in regions where HIV infection is common are at high risk of acquiring HIV infection during pregnancy and the postpartum period and that mothers who acquire HIV during pregnancy or postpartum are more likely to pass the infection on to their offspring than mothers with chronic HIV infections. However, the small number of studies included in this meta-analysis and the use of heterogeneous research methodologies in these studies may limit the accuracy of these findings. Nevertheless, these findings have important implications for the global plan to eliminate HIV infections in children. First, they suggest that women living in regions where HIV infection is common should be offered repeat HIV testing (using sensitive methods to enhance early detection of infection) during pregnancy and in the postpartum period to detect incident HIV infections, and should be promptly referred to HIV care and treatment. Second, they suggest that prevention of HIV transmission during pregnancy and postpartum should be prioritized, for example, by counseling women about the need to use condoms to prevent transmission during this period of their lives.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001608.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on children and HIV/AIDS and on the prevention of mother-to-child transmission of HIV (in English and Spanish)
The 2013 UNAIDS World AIDS Day Report provides information about the AIDS epidemic and efforts to halt it; the 2013 UNAIDS Progress Report on the Global Plan provides information on progress towards eliminating new HIV infections among children; the UNAIDS Believe it. Do it website provides information about the campaign to support the UNAIDS global plan
Personal stories about living with HIV/AIDS, including stories from young people infected with HIV, are available through Avert, NAM/aidsmap, and Healthtalkonline
doi:10.1371/journal.pmed.1001608
PMCID: PMC3934828  PMID: 24586123
15.  Receipt of Opioid Analgesics by HIV-Infected and Uninfected Patients 
ABSTRACT
BACKGROUND
Opioids are increasingly prescribed, but there are limited data on opioid receipt by HIV status.
OBJECTIVES
To describe patterns of opioid receipt by HIV status and the relationship between HIV status and receiving any, high-dose, and long-term opioids.
DESIGN
Cross-sectional analysis of the Veterans Aging Cohort Study.
PARTICIPANTS
HIV-infected (HIV+) patients receiving Veterans Health Administration care, and uninfected matched controls.
MAIN MEASURES
Pain-related diagnoses were determined using ICD-9 codes. Any opioid receipt was defined as at least one opioid prescription; high-dose was defined as an average daily dose ≥120 mg of morphine equivalents; long-term opioids was defined as ≥90 consecutive days, allowing a 30 day refill gap. Multivariable models were used to assess the relationship between HIV infection and the three outcomes.
KEY RESULTS
Among the HIV+ (n = 23,651) and uninfected (n = 55,097) patients, 31 % of HIV+ and 28 % of uninfected (p < 0.001) received opioids. Among patients receiving opioids, HIV+ patients were more likely to have an acute pain diagnosis (7 % vs. 4 %), but less likely to have a chronic pain diagnosis (53 % vs. 69 %). HIV+ patients received a higher mean daily morphine equivalent dose than uninfected patients (41 mg vs. 37 mg, p = 0.001) and were more likely to receive high-dose opioids (6 % vs. 5 %, p < 0.001). HIV+ patients received fewer days of opioids than uninfected patients (median 44 vs. 60, p < 0.001), and were less likely to receive long-term opioids (31 % vs. 34 %, p < 0.001). In multivariable analysis, HIV+ status was associated with receipt of any opioids (AOR 1.40, 95 % CI 1.35, 1.46) and high-dose opioids (AOR 1.22, 95 % CI 1.07, 1.39), but not long-term opioids (AOR 0.94, 95 % CI 0.88, 1.01).
CONCLUSIONS
Patients with HIV infection are more likely to be prescribed opioids than uninfected individuals, and there is a variable association with pain diagnoses. Efforts to standardize approaches to pain management may be warranted in this highly complex and vulnerable patient population.
doi:10.1007/s11606-012-2189-z
PMCID: PMC3539026  PMID: 22895747
opioid; pain; HIV; narcotics; veterans
16.  HIV among People Who Inject Drugs in the Middle East and North Africa: Systematic Review and Data Synthesis 
PLoS Medicine  2014;11(6):e1001663.
Laith Abu-Raddad and colleagues assess the current state of knowledge of the HIV epidemic among people who inject drugs in the Middle East and North Africa.
Please see later in the article for the Editors' Summary
Background
It is perceived that little is known about the epidemiology of HIV infection among people who inject drugs (PWID) in the Middle East and North Africa (MENA). The primary objective of this study was to assess the status of the HIV epidemic among PWID in MENA by describing HIV prevalence and incidence. Secondary objectives were to describe the risk behavior environment and the HIV epidemic potential among PWID, and to estimate the prevalence of injecting drug use in MENA.
Methods and Findings
This was a systematic review following the PRISMA guidelines and covering 23 MENA countries. PubMed, Embase, regional and international databases, as well as country-level reports were searched up to December 16, 2013. Primary studies reporting (1) the prevalence/incidence of HIV, other sexually transmitted infections, or hepatitis C virus (HCV) among PWIDs; or (2) the prevalence of injecting or sexual risk behaviors, or HIV knowledge among PWID; or (3) the number/proportion of PWID in MENA countries, were eligible for inclusion. The quality, quantity, and geographic coverage of the data were assessed at country level. Risk of bias in predefined quality domains was described to assess the quality of available HIV prevalence measures. After multiple level screening, 192 eligible reports were included in the review. There were 197 HIV prevalence measures on a total of 58,241 PWID extracted from reports, and an additional 226 HIV prevalence measures extracted from the databases.
We estimated that there are 626,000 PWID in MENA (range: 335,000–1,635,000, prevalence of 0.24 per 100 adults). We found evidence of HIV epidemics among PWID in at least one-third of MENA countries, most of which are emerging concentrated epidemics and with HIV prevalence overall in the range of 10%–15%. Some of the epidemics have however already reached considerable levels including some of the highest HIV prevalence among PWID globally (87.1% in Tripoli, Libya). The relatively high prevalence of sharing needles/syringes (18%–28% in the last injection), the low levels of condom use (20%–54% ever condom use), the high levels of having sex with sex workers and of men having sex with men (15%–30% and 2%–10% in the last year, respectively), and of selling sex (5%–29% in the last year), indicate a high injecting and sexual risk environment. The prevalence of HCV (31%–64%) and of sexually transmitted infections suggest high levels of risk behavior indicative of the potential for more and larger HIV epidemics.
Conclusions
Our study identified a large volume of HIV-related biological and behavioral data among PWID in the MENA region. The coverage and quality of the data varied between countries. There is robust evidence for HIV epidemics among PWID in multiple countries, most of which have emerged within the last decade and continue to grow. The lack of sufficient evidence in some MENA countries does not preclude the possibility of hidden epidemics among PWID in these settings. With the HIV epidemic among PWID in overall a relatively early phase, there is a window of opportunity for prevention that should not be missed through the provision of comprehensive programs, including scale-up of harm reduction services and expansion of surveillance systems.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 35 million people worldwide are currently infected with HIV, the virus that causes AIDS, and around 2.3 million people become newly infected every year. HIV is mainly transmitted through unprotected sex with an infected partner. However, people who inject drugs (PWID) have a particularly high risk of HIV infection because blood transfer through needle and syringe sharing can transmit the virus. Worldwide, 5%–10% of all HIV-positive people are PWID but in some regions of the world the fraction of all HIV-positive people that are PWID is even higher. To meet the global health challenge of the high HIV prevalence (the proportion of a population that has a specific disease) among PWID, the Joint United Nations Programme on HIV/AIDS (UNAIDS) and other international bodies endorse harm reduction strategies to prevent risky injection behaviors among PWID. These strategies include education and the provision of clean needles, syringes, and opioid substitution therapy.
Why Was This Study Done?
To maximize the effect of these harm-reduction strategies in specific regions, it is important to understand the status of the HIV epidemic among PWID. Although surveillance systems provide the information on HIV infection needed to track the progress of HIV epidemics among PWID in many regions, little is known about the HIV epidemic among PWID in the Middle East and North Africa (MENA, a geographical region that encompasses countries that share historical, socio-cultural, linguistic, and religious characteristics). Several factors contribute to the likelihood of individuals injecting drugs in MENA. For example, Afghanistan (a MENA country) produces most of the world's supply of heroin, which is largely trafficked through Iran and Pakistan (also MENA countries). In this systematic review and data synthesis, the researchers use predefined criteria to identify all the published and unpublished data on HIV prevalence and incidence (the number of new cases of a disease in a population in a given time) among PWID in MENA and combine (synthesize) these data to assess the status of the HIV epidemic in this key population for HIV transmission in MENA.
What Did the Researchers Do and Find?
The researchers identified 192 reports that reported the prevalence/incidence of HIV, other sexually transmitted infections and infection with hepatitis C virus (HCV, another virus transmitted through drug injection) among PWID, the prevalence of injecting or sexual risk behaviors among PWID, or the number/proportion of PWID in MENA. From these data, the researchers estimated that there are about 600,000 PWID in MENA (a prevalence of 0.24 per 100 adults, which is comparable with figures from other regions). The data provided evidence for HIV epidemics among PWID in at least a third of MENA countries, mainly emerging concentrated epidemics (epidemics that are still growing but in which HIV infection and transmission are already considerable). HIV prevalence among PWID in MENA varied considerably, reaching an extremely high prevalence of 87.1% in Tripoli, Libya. The data also revealed a high injecting and sexual risk environment among PWID in MENA (for example, on average, about a quarter of PWID shared a needle or syringe in their most recent injection and only a third reported ever using condoms) that, together with a high prevalence of HCV and sexually transmitted infections among PWID, indicates the potential for more and larger HIV epidemics.
What Do These Findings Mean?
These findings indicate that substantial amounts of HIV-related data have been collected from PWID in MENA but that the coverage and quality of these data vary widely between countries. They provide robust evidence for growing HIV epidemics, most of which have emerged within the past decade, among PWID in several MENA countries, but do not preclude the possibility of hidden epidemics among PWID in additional MENA countries. Overall, these findings suggest that the HIV epidemic among PWID in MENA is at a relatively early stage. This window of opportunity to control the emerging epidemics should not be missed, warn the researchers. HIV surveillance among PWID in MENA must be expanded to detect and monitor emerging and growing HIV epidemics, they suggest, and to inform effective HIV policy and programming. Improvements in HIV prevention and treatment among PWID in MENA are essential, they conclude, to confront the growing HIV problem in this population and, to prevent the onward transmission of HIV from PWID to other population groups.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001663.
A 2010 report produced by the World Bank, UNAIDS, and WHO provides information on the status of the HIV epidemic in the Middle East and North Africa; the UNAIDS Middle East and North Africa Regional Report on AIDS 2011 provides further information
The 2013 UNAIDS World AIDS Day Report provides up-to-date information about the AIDS epidemic and efforts to halt it
The Middle East and North Africa Harm Reduction Association (MENAHRA) provides information about harm reduction efforts, services, and programs in the Middle East and North Africa; Harm Reduction International provides information about harm reduction concepts, strategies, programs, and publications globally
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on people who inject drugs and HIV/AIDS and on harm reduction and HIV prevention (in English and Spanish)
The US National Institute on Drug Abuse also provides information about drug abuse and HIV/AIDS (in English and Spanish)
Personal stories about living with HIV/AIDS are available through Avert, Nam/aidsmap, and Healthtalkonline
doi:10.1371/journal.pmed.1001663
PMCID: PMC4061009  PMID: 24937136
17.  Hepatitis C virus screening practices and seropositivity among US veterans born during 1945 – 1965 
BMC Research Notes  2014;7:449.
Background
The Centers for Disease Control and Prevention (CDC) and the United States Preventive Services Task Force (USPSTF) recently augmented risk-based hepatitis C (HCV) screening guidelines with a recommendation to perform one-time screening in all persons born during 1945 – 1965, a birth cohort known to have a higher prevalence of HCV. We sought to estimate the proportion of veterans seen at the Atlanta VA Medical Center (AVAMC) who had ever been screened for HCV infection by birth year.
Methods
We used an administrative database of all veterans seen at the AVAMC between January 1, 2011 and December 31, 2011, and a laboratory generated list of all HCV antibody tests and HCV RNA viral loads that were performed at the AVAMC to determine receipt of screening and HCV antibody positivity. Odds ratios and 95% confidence intervals were estimated using SAS version 9.2 (SAS institute, Cary, North Carolina).
Results
HCV antibody testing had ever been performed on 48% (41,556) of the veterans seen in 2011; 10% of those tested had a positive antibody. Confirmatory viral loads were performed in 96% of those with a positive antibody screen. Those born during 1945 – 1965 were more likely to have a HCV antibody performed when compared with those born in other years (54% vs. 41%, odds ratio [OR] 1.70, 95% Confidence Interval [CI] 1.65-1.74). Among veterans ever tested for HCV antibody (n = 41,556), those born during 1945 – 1965 were 6 times more likely to have a positive HCV antibody (15% vs. 3%, OR 5.87, 95% CI 5.32-6.78), and 3 times more likely to have chronic HCV infection (76% vs. 50%, OR 3.25, 95% CI 2.65-4.00).
Conclusions
Nearly half of the veterans seen in 2011 at the AVAMC had ever been tested for HCV infection. When examined by birth cohort, over half of the veterans born during 1945 – 1965 had been screened for HCV and 15% of those screened had a positive HCV antibody. Our findings confirm the increased prevalence of HCV infection in persons born during 1945 – 1965 as identified in the updated CDC and USPSTF recommendations.
doi:10.1186/1756-0500-7-449
PMCID: PMC4105869  PMID: 25023159
Hepatitis C; Screening; Prevention & control
18.  Medical ICU Admission Diagnoses and Outcomes in Human Immunodeficiency Virus–Infected and Virus–Uninfected Veterans in the Combination Antiretroviral Era 
Critical care medicine  2013;41(6):1458-1467.
Objectives
Human immunodeficiency virus (HIV)–infected (HIV+) patients on combination antiretroviral therapy are living longer but have increased risk for aging-associated disease which may lead to increasing critical care requirements. We compare medical ICU admission characteristics and outcomes among HIV infected and demographically similar uninfected patients (uninfected) and considered whether an index which combines routine clinical biomarkers (the Veterans Aging Cohort Study Index) predicts 30-day medical ICU mortality.
Design
Observational data analyses (Veterans Aging Cohort Study).
Setting
Eight Veterans Affairs medical centers nationwide.
Patients
HIV infected and uninfected with a medical ICU admission between 2002 and 2010.
Intervention
None.
Measurements and Main Results
Medical ICU admission was determined using bedsection (Veterans Affairs) and revenue center codes (Medicare). For Veterans Affairs admissions, we used clinical data to calculate Veterans Aging Cohort Study Index scores and multivariable logistic regression to determine factors associated with 30-day mortality. Overall, 539 of 3,620 (15%) HIV infected and 375 of 3,639 (10%) uninfected had a medical ICU admission; 72% and 78%, respectively, were Veterans Affairs based. HIV+ patients were younger at admission (p < 0.0001). Although most HIV+ patients were on antiretroviral therapy (71%) with undetectable HIV-1 RNA (54%), compared with uninfected they were more commonly admitted with respiratory diagnoses or infections (21% vs. 12%), were more likely to require mechanical ventilation (17% vs. 9%; p = 0.001), and had a higher mortality rate (18.6% vs. 11.2%, p = 0.003). Cardiovascular diagnoses were less common among HIV infected (18% vs. 29%; p < 0.0001). In logistic regression (c-statistic 0.87), a 5-point increment in Veterans Aging Cohort Study Index was associated with an odds ratio of death of 1.22 (95% confidence interval 1.14–1.30) among HIV infected and of 1.50 (95% confidence interval 1.29–1.76) among uninfected; infection/sepsis and respiratory diagnoses were also associated with mortality.
Conclusions
Medical ICU admission was frequent, 30-day mortality higher, and mechanical ventilation more common in HIV infected compared with uninfected. The Veterans Aging Cohort Study Index calculated at medical ICU admission predicted 30-day mortality for HIV infected and uninfected. As more individuals age with HIV, their requirements for medical ICU care may be greater than demographically similar uninfected individuals.
doi:10.1097/CCM.0b013e31827caa46
PMCID: PMC4283206  PMID: 23507717
30-day mortality; comorbidity; human immunodeficiency virus; medical ICU; Veterans Aging Cohort Study Index
19.  Medicare and Medicaid enrollment and outside hospitalizations among HIV-infected and uninfected veterans engaged in VA care: a retrospective cohort study 
Background
Many veterans engaged in care with the Veterans Administration (VA) health system are also enrolled in Medicare and/or Medicaid and may receive care both inside and outside of the VA. Use of dual health systems has been associated with worse outcomes. Veterans with HIV may have different rates of Medicare and Medicaid enrollment and may be at greater risk of poor outcomes related to non-VA use. This study compares the frequency and factors associated with Medicare and/or Medicaid enrollment and non-VA use in an HIV-infected and uninfected population of veterans.
Methods
We used data from the VA and Center for Medicare & Medicaid Services from 2004 and 2005 to determine the frequency of Medicare and/or Medicaid enrollment among a cohort of HIV-infected and uninfected veterans engaged in VA care. We then restricted the cohort to veterans enrolled in fee-for-service (FFS) Medicare and/or Medicaid with at least one hospitalization and identified characteristics associated with non-VA hospital admissions.
Results
HIV-infected veterans had higher rates of Medicare and/or Medicaid enrollment than uninfected veterans (38% vs. 33%, p < 0.01), though the opposite was true when our sample was limited to veterans 65 years and older (53% vs. 70%, p < 0.0 1). Among veterans enrolled in the VA and FFS Medicare and/or Medicaid, veterans with HIV had greater illness severity and more frequent hospitalizations, but were less likely to be hospitalized outside the VA (48% vs. 54%, p < 0.01). HIV infection was associated with lower odds of outside hospitalization (OR = 0.76 [95% CI: 0.68, 0.85]).
Conclusions
Veterans with HIV have higher rates of Medicare and/or Medicaid enrollment, but lower odds of non-VA hospitalization. The VA integrated model of HIV care may discourage outside use among HIV-infected veterans.
doi:10.1186/s12913-015-0684-8
PMCID: PMC4307747  PMID: 25608566
HIV; AIDS; Veterans; Medicare; Medicaid; Fragmentation
20.  Prehypertension, Hypertension, and the Risk of Acute Myocardial Infarction in HIV-Infected and -Uninfected Veterans 
We found increased acute myocardial infarction risk among hypertensive and prehypertensive HIV-infected veterans compared to normotensive uninfected veterans, independent of confounding comorbidities.
Background. Compared to uninfected people, human immunodeficiency virus (HIV)–infected individuals may have an increased risk of acute myocardial infarction (AMI). Currently, HIV-infected people are treated to the same blood pressure (BP) goals (<140/90 or <130/80 mm Hg) as their uninfected counterparts. Whether HIV-infected people with elevated BP have excess AMI risk compared to uninfected people is not known. This study examines whether the association between elevated BP and AMI risk differs by HIV status.
Methods. The Veterans Aging Cohort Study Virtual Cohort (VACS VC) consists of HIV-infected and -uninfected veterans matched 1:2 on age, sex, race/ethnicity, and clinical site. For this analysis, we analyzed 81 026 people with available BP data from VACS VC, who were free of cardiovascular disease at baseline. BP was the average of the 3 routine outpatient clinical measurements performed closest to baseline (first clinical visit after April 2003). BP categories used in the analyses were based on criteria of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Analyses were performed using Cox proportional hazards regression.
Results. Over 5.9 years (median), 860 incident AMIs occurred. Low/high prehypertensive and untreated/treated hypertensive HIV-infected individuals had increased AMI risk compared to uninfected, untreated normotensive individuals (hazard ratio [HR], 1.60 [95% confidence interval {CI}, 1.07–2.39]; HR, 1.81 [95% CI, 1.22–2.68]; HR, 2.57 [95% CI, 1.76–3.76]; and HR, 2.76 [95% CI, 1.90–4.02], respectively).
Conclusions. HIV, prehypertensive BP, and hypertensive BP were associated with an increased risk of AMI in a cohort of HIV-infected and -uninfected veterans. Future studies should prospectively investigate whether HIV interacts with BP to further increase AMI risk.
doi:10.1093/cid/cit652
PMCID: PMC3864500  PMID: 24065316
blood pressure; prehypertension; HIV; myocardial infarction
21.  No Treatment versus 24 or 60 Weeks of Antiretroviral Treatment during Primary HIV Infection: The Randomized Primo-SHM Trial 
PLoS Medicine  2012;9(3):e1001196.
In a three-arm randomized trial conducted among adult patients in HIV treatment centers in The Netherlands, Marlous Grijsen and colleagues examine the effects of temporary combination antiretroviral therapy during primary HIV infection.
Background
The objective of this study was to assess the benefit of temporary combination antiretroviral therapy (cART) during primary HIV infection (PHI).
Methods and Findings
Adult patients with laboratory evidence of PHI were recruited in 13 HIV treatment centers in the Netherlands and randomly assigned to receive no treatment or 24 or 60 wk of cART (allocation in a 1∶1∶1 ratio); if therapy was clinically indicated, participants were randomized over the two treatment arms (allocation in a 1∶1 ratio). Primary end points were (1) viral set point, defined as the plasma viral load 36 wk after randomization in the no treatment arm and 36 wk after treatment interruption in the treatment arms, and (2) the total time that patients were off therapy, defined as the time between randomization and start of cART in the no treatment arm, and the time between treatment interruption and restart of cART in the treatment arms. cART was (re)started in case of confirmed CD4 cell count <350 cells/mm3 or symptomatic HIV disease. In total, 173 participants were randomized. The modified intention-to-treat analysis comprised 168 patients: 115 were randomized over the three study arms, and 53 randomized over the two treatment arms. Of the 115 patients randomized over the three study arms, mean viral set point was 4.8 (standard deviation 0.6) log10 copies/ml in the no treatment arm, and 4.0 (1.0) and 4.3 (0.9) log10 copies/ml in the 24- and 60-wk treatment arms (between groups: p<0.001). The median total time off therapy in the no treatment arm was 0.7 (95% CI 0.0–1.8) y compared to 3.0 (1.9–4.2) and 1.8 (0.5–3.0) y in the 24- and 60-wk treatment arms (log rank test, p<0.001). In the adjusted Cox analysis, both 24 wk (hazard ratio 0.42 [95% CI 0.25–0.73]) and 60 wk of early treatment (hazard ratio 0.55 [0.32–0.95]) were associated with time to (re)start of cART.
Conclusions
In this trial, temporary cART during PHI was found to transiently lower the viral set point and defer the restart of cART during chronic HIV infection.
Trial registration
Current Controlled Trials ISRCTN59497461
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, nearly three million people become infected with HIV, the virus that causes AIDS. The first stage of HIV infection—primary HIV infection—lasts a few weeks and often goes undetected, although most individuals develop a short, flu-like illness. During this stage of infection, the immune system begins to make antibodies to HIV. The second stage of HIV infection, which lasts many years, also has no major symptoms but, during this stage, HIV slowly destroys immune system cells, including CD4 cells, a type of lymphocyte. Eventually, the immune system is unable to fight off other infections and patients enter the third phase of HIV infection—symptomatic HIV infection. The final stage—AIDS—is characterized by the occurrence of one or more AIDS-defining conditions, which include severe but unusual infections and several types of cancer. Early in the AIDS epidemic, most HIV-positive people died within ten years of infection. Nowadays, although there is still no cure for HIV infection, HIV has become a chronic disease because of the availability of combination antiretroviral therapy (cART; cocktails of several powerful drugs). This means that many HIV-positive people have a near-normal life span.
Why Was This Study Done?
It is currently recommended that people start cART when their CD4 count falls below 350 CD4 cells per cubic milliliter (cells/mm3) of blood, when they develop severe constitutional symptoms such as fever lasting longer than a month, or when they develop an AIDS-defining condition. But could a short course of cART during primary HIV infection be clinically beneficial? Some, but not all, nonrandomized studies have shown that such treatment reduces the viral set point (the stabilized viral load that is reached after the immune system begins to make antibodies to HIV; the viral load is the amount of virus in the blood) and slows the decline of CD4 cell count in patients. In this randomized trial (the Primo-SHM trial), the researchers assess the clinical benefit of temporary cART initiated during primary HIV infection by measuring its effects on the viral set point and on when patients have to restart cART during chronic HIV infection. In a randomized controlled trial, patients are assigned by the play of chance to receive different treatments and then followed to compare the effects of these treatments.
What Did the Researchers Do and Find?
The researchers assigned 168 patients with primary HIV infection to receive no treatment, 24 weeks of cART, or 60 weeks of cART. They measured the viral set point (the viral load in the blood 36 weeks after randomization in the no treatment arm and 36 weeks after cART interruption in the treatment arms) and determined the time off therapy (the time between randomization and the start of cART in the no treatment arm, and the time between treatment interruption and restart of cART in the treatment arms) for each patient. cART was (re)started following two consecutive CD4 counts below 350 cells/mm3 or when symptomatic HIV disease developed. The average viral set point was lower in the patients who received early cART than in those who had no treatment. Moreover, on average, the patients in the no treatment arm started cART 0.7 years after randomization whereas those in the 24- and 60-week treatment arms restarted cART after 3.0 and 1.8 years, respectively. There was no statistically significant difference between the 24-week and 60-week treatment arms in time off therapy.
What Do These Findings Mean?
These findings suggest that temporary cART during primary HIV infection can transiently lower the viral set point and can delay the need to restart cART during chromic HIV infection. They also suggest that 24 weeks of cART during primary HIV is as effective as 60 weeks of treatment. These findings need to be confirmed in other settings, and follow-up studies are needed to evaluate the long-term benefits of early temporary cART, but given the short time between cART interruption and treatment restart, the researchers suggest that not interrupting early cART, but instead continuing it for life, should be considered. However, they add, because patients are often physically and emotionally distressed at this stage of HIV infection, adherence to cART during primary HIV infection may be suboptimal, and so patients with primary HIV infection should be advised to start cART only when they feel ready to start treatment.
Additional Information
Please access these web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001196.
Information is available from the US National Institute of Allergy and infectious diseases on HIV infection and AIDS, including information on the clinical progression of HIV infection
NAM/aidsmap provides information about HIV/AIDS, including a factsheet on primary infection
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including detailed information on HIV treatment and care and on the stages of HIV infection (in English and Spanish)
The World Health Organization's 2010 antiretroviral therapy guidelines provide recommendations on when to initiate cART
Information about Primo-SHM is available
Patient stories about living with HIV/AIDS are available through Avert and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001196
PMCID: PMC3313945  PMID: 22479156
22.  Hepatitis C Virus Infection and the Risk of Coronary Disease 
Background
The association between hepatitis C virus (HCV) infection and coronary artery disease (CAD) is controversial. We conducted this study to determine and quantify this association.
Methods
We used an established, national, observational cohort of all HCV-infected veterans receiving care at all Veterans Affairs facilities, the Electronically Retrieved Cohort of HCV Infected Veterans, to identify HCV-infected subjects and HCV-uninfected control subjects. We used the Cox proportional-hazards model to determine the risk of CAD among HCV-infected subjects and control subjects.
Results
We identified 82,083 HCV-infected and 89,582 HCV-uninfected subjects. HCV-infected subjects were less likely to have hypertension, hyperlipidemia, and diabetes but were more likely to abuse alcohol and drugs and to have renal failure and anemia. HCV-infected subjects had lower mean (± standard deviation) total plasma cholesterol (175 ± 40.8 mg/dL vs. 198 ± 41.0 mg/dL), low-density lipoprotein cholesterol (102 ± 36.8 mg/dL vs. 119 ± 38.2 mg/dL), and triglyceride (144 ± 119 mg/dL vs. 179 ± 151 mg/dL) levels, compared with HCV-uninfected subjects. In multivariable analysis, HCV infection was associated with a higher risk of CAD (hazard ratio, 1.25; 95% confidence interval, 1.20–1.30; P < .001 for all comparisons). Traditional risk factors (age, hypertension, chronic obstructive pulmonary disease, diabetes, and hyperlipidemia) were associated with a higher risk of CAD in both groups, whereas minority race and female sex were associated with a lower risk of CAD.
Conclusions
HCV-infected persons are younger and have lower lipid levels and a lower prevalence of hypertension. Despite a favorable risk profile, HCV infection is associated with a higher risk of CAD after adjustment for traditional risk factors.
doi:10.1086/599371
PMCID: PMC3077953  PMID: 19508169
23.  Does social isolation predict hospitalization and mortality among HIV+ and uninfected older Veterans? 
Background and Objectives
Aging, HIV, and social isolation may affect acute care utilization and outcomes. Our objectives were to compare levels of social isolation in aging Veterans with and without HIV and determine associations with hospital admission and mortality.
Study Design, Participants, and Setting
The Veterans Aging Cohort Study (VACS) is a longitudinal study of HIV+ and uninfected Veterans at eight VA Medical Centers nationally. We analyzed data for 1,836 Veterans age ≥55 enrolled in VACS from 2002–2008.
Measurements
We created a Social Isolation Score (SIS) using baseline survey responses about: relationship status, number of friends/family and frequency of visits, and involvement in volunteer work, religious or self-help groups, or other community activities. We compared scores by age and HIV status and used multivariable regression to assess effects of social isolation scores on hospital admission and all-cause mortality.
Results
Mean SIS was higher for HIV+ patients with increasing difference by age (p=.01 for trend). Social isolation was also more prevalent for HIV+ (59%) compared to uninfected patients (51%; p<.001). In multivariable regression analysis of HIV+ and uninfected groups combined, adjusted for demographic and clinical features, isolation was independently associated with increased risk of incident hospitalization (HR=1.25, 95% CI=1.09–1.42) as well as risk of all-cause mortality (HR=1.28, 95% CI=1.06–1.54). Risk estimates calculated for HIV+ and uninfected groups separately were not significantly different.
Conclusions
Social isolation is associated with increased risk of hospitalization and death among both HIV+ and uninfected older Veterans. Despite similar effects in both groups, the population level impact of social isolation may be greater in those who are HIV+ because of the higher prevalence of social isolation, particularly among the oldest patients.
doi:10.1111/jgs.12410
PMCID: PMC3773301  PMID: 23927911
Social isolation; aging; HIV/AIDS; hospitalization; mortality; outcomes of care
24.  Hepatitis C and the Risk of Kidney Disease and Mortality in Veterans With HIV 
Objectives
To examine the effect of hepatitis C virus (HCV) on the prevalence of chronic kidney disease (CKD) among veterans with HIV and to evaluate independent associations of HCV and CKD with mortality.
Methods
We studied a national cohort of HIV-infected patients receiving care through the Veterans Healthcare Administration from 1998 to 2004. CKD was defined as an estimated glomerular filtration rate [eGFR (mL/min/1.73 m2)] < 60. Poisson regression was used to assess relationships between CKD, HCV, and mortality.
Results
Among 23,155 HIV-infected veterans, 12% had CKD. Forty percent of the cohort was coinfected with HCV, and a higher proportion of coinfected subjects had CKD compared with monoinfected subjects (14% vs 11%, P < 0.001). During the median follow-up of 7.6 years, 37% of subjects died and a graduated increase in adjusted mortality rates occurred with lower levels of eGFR (P < 0.001). Adjusted mortality rates were consistently higher in HCV-coinfected subjects across all levels of eGFR (P < 0.001). HCV was independently associated with increased mortality (incidence rate ratio 1.23, 95% confidence interval 1.17–1.29).
Conclusions
CKD is prevalent in HIV-infected veterans and associated with substantially higher mortality. Compared with their monoinfected counterparts, veterans coinfected with HCV have significantly higher rates of CKD and mortality.
doi:10.1097/QAI.0b013e3181b980d4
PMCID: PMC3032564  PMID: 20104121
death; HIV; hepatitis C; kidney failure; veterans
25.  Time to Depression Treatment in Primary Care Among HIV-infected and Uninfected Veterans 
BACKGROUND
Multiple factors, including patient characteristics, competing demands, and clinic type, impact delivery of depression treatment in primary care.
OBJECTIVE
Assess whether depression severity and HIV serostatus have a differential effect on time to depression treatment among depressed patients receiving primary care at Infectious Disease or General Medicine clinics.
DESIGN
Multicenter prospective cohort, (Veterans Aging Cohort Study), comparing HIV-infected to uninfected patients.
PARTICIPANTS AND MEASURES
The total cohort consisted of 3,239 HIV-infected and 3,227 uninfected patients. Study inclusion criteria were untreated depressive symptoms, based on a Patient Health Questionnaire (PHQ-9) score of greater than 9, and no antidepressants or mental health visits in the 90 days prior to PHQ-9 assessment. Treatment was defined as antidepressant receipt or mental health visit within 90 days following PHQ-9 assessment. Depression severity based on PHQ-9 scores was defined as mild-moderate (greater than 9 to 19) and severe (20 or greater). Kaplan-Meier curves were used to estimate time to treatment by depression severity and HIV serostatus. Cox proportional hazards methods adjusted for covariates were used.
KEY RESULTS
Overall, 718 (11%) of the cohort met inclusion criteria, 258 (36%) of whom received treatment. Median time to treatment was 7 days [95% confidence interval (CI) = 4, 13] and was shortest for severely depressed HIV-infected patients (0.5 days; 95% CI = 0.5, 6, p = 0.04). Compared to mildly-moderately depressed uninfected patients, severely depressed HIV-infected patients were significantly more likely to receive treatment [adjusted hazard ratio (HR) 1.67, 95% CI = 1.07, 2.60), whereas mildly-moderately depressed HIV-infected patients (adjusted HR 1.10, 95% CI = 0.79, 1.52) and severely depressed uninfected patients (adjusted HR 0.93, 95% CI = 0.60, 1.44) were not.
CONCLUSIONS
In this large cohort, time to primary care treatment of depression was shortest among severely depressed HIV-infected patients. Regardless of HIV serostatus, if depression was not treated on the assessment day, then it was unlikely to be treated within a 90-day period, leading to the majority of depression being untreated.
doi:10.1007/s11606-010-1323-z
PMCID: PMC2881956  PMID: 20405335
AIDS; antidepressant drugs; HIV; major depression; psychotherapy

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