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1.  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
2.  HIV Impairs Opsonic Phagocytic Clearance of Pregnancy-Associated Malaria Parasites 
PLoS Medicine  2007;4(5):e181.
Background
Primigravid (PG) women are at risk for pregnancy-associated malaria (PAM). Multigravid (MG) women acquire protection against PAM; however, HIV infection impairs this protective response. Protection against PAM is associated with the production of IgG specific for variant surface antigens (VSA-PAM) expressed by chondroitin sulfate A (CSA)-adhering parasitized erythrocytes (PEs). We hypothesized that VSA-PAM-specific IgG confers protection by promoting opsonic phagocytosis of PAM isolates and that HIV infection impairs this response.
Methods and Findings
We assessed the ability of VSA-PAM-specific IgG to promote opsonic phagocytosis of CSA-adhering PEs and the impact of HIV infection on this process. Opsonic phagocytosis assays were performed using the CSA-adherent parasite line CS2 and human and murine macrophages. CS2 PEs were opsonized with plasma or purified IgG subclasses from HIV-negative or HIV-infected PG and MG Kenyan women or sympatric men. Levels of IgG subclasses specific for VSA-PAM were compared in HIV-negative and HIV-infected women by flow cytometry. Plasma from HIV-negative MG women, but not PG women or men, promoted the opsonic phagocytosis of CSA-binding PEs (p < 0.001). This function depended on VSA-PAM-specific plasma IgG1 and IgG3. HIV-infected MG women had significantly lower plasma opsonizing activity (median phagocytic index 46 [interquartile range (IQR) 18–195] versus 251 [IQR 93–397], p = 0.006) and levels of VSA-PAM-specific IgG1 (mean fluorescence intensity [MFI] 13 [IQR 11–20] versus 30 [IQR 23–41], p < 0.001) and IgG3 (MFI 17 [IQR 14–23] versus 28 [IQR 23–37], p < 0.001) than their HIV-negative MG counterparts.
Conclusions
Opsonic phagocytosis may represent a novel correlate of protection against PAM. HIV infection may increase the susceptibility of multigravid women to PAM by impairing this clearance mechanism.
Based on a comparison of HIV-negative or HIV-infected primigravid and multigravid women, Kevin Kain and colleagues suggest that opsonic phagocytosis might protect against pregnancy-associated malaria, and that HIV infection might impair this parasite clearance mechanism.
Editors' Summary
Background.
Every year, malaria kills more than one million people—mostly young children. Among adults, pregnant women are most affected by malaria, a parasitic disease spread by mosquitos. In areas of Africa where malaria is widespread, about 10,000 women die because of pregnancy-associated malaria (PAM) each year. In PAM, red blood cells containing parasites (parasitized erythrocytes or PEs) collect in the woman's placenta. These PEs, which stick to a placental molecule called chondroitin sulfate A (CSA), are covered with parasitic proteins known as variant surface antigens of PAM (VSA-PAM). Women in their first pregnancy (primigravid women) are particularly susceptible to PAM, but multigravid women are more resistant unless they are also infected with HIV (the virus that causes AIDS), in which case they are extremely susceptible to PAM. Protection against PAM in multigravid women is associated with the production of immunoglobulins (proteins made by the immune system that circulate in the blood and bind to foreign proteins or antigens) that recognize VSA-PAM. These immunoglobulins or antibodies are called VSA-PAM-specific IgG and their production increases with each pregnancy
Why Was This Study Done?
It is unclear how VSA-PAM-specific IgG protects multigravid women against PAM or how HIV infection impairs this protective response. One possibility is that VSA-PAM-specific IgG coats the PEs in the placenta to enable immune system cells called macrophages to recognize and ingest them, a process called opsonic phagocytosis. In this study, the researchers have investigated whether opsonic phagocytosis provides multigravid women with protection against PAM and whether a failure of this form of protective immunity underlies the susceptibility of HIV-infected multigravid women to PAM.
What Did the Researchers Do and Find?
The researchers collected plasma (the fluid part of blood) from primigravid and multigravid women (some of whom were infected with HIV) living in a Kenyan region where malaria is common soon after they gave birth and from men living in the same area. They then purified IgG1, IgG2, IgG3, and IgG4 from the plasma samples. These four IgG subclasses have different immune functions—only IgG1 and IgG3 participate in opsonic phagocytosis. To measure the ability of the plasma samples and purified IgGs to promote opsonic phagocytosis, the researchers mixed each sample with a laboratory isolate of CSA-binding PEs and macrophages and counted how many PEs the macrophages ingested. Plasma from HIV-negative multigravid women but not primigravid women or men promoted opsonic phagocytosis and, in the plasma from multigravid women, this activity depended on IgG1 and IgG3. HIV-infected multigravid women, however, had less opsonizing activity in their plasma than HIV-negative multigravid women and the level of this activity correlated with the levels of VSA-PAM-specific IgG1 and IgG3 (measured using a technique called flow cytometry) in the plasma samples of these two groups of women.
What Do These Findings Mean?
These findings support the hypothesis that VSA-PAM-specific IgG1 and IgG3 promote opsonic clearance of CSA-binding PEs. Thus, opsonic immune mechanisms may be involved in the protective response to PAM seen in multigravid women. However, because all the measurements of opsonic phagocytosis in this study used a laboratory isolate of PEs, these findings need to be confirmed using PEs isolated from placentas to check that they are generalizable. Other findings reported here suggest that HIV-positive multigravid women are more susceptible to PAM than HIV-negative multigravid women because reduced amounts of VSA-PAM-specific IgG in their plasma reduce the ability of opsonic phagocytosis to clear PEs from their placenta. Overall, these results may have implications for the development of vaccines against PAM. For example, they suggest that vaccines should be designed to stimulate the production of VSA-PAM-specific antibodies of the IgG1 and IgG3 subclasses. They also suggest that, provided the link between opsonic phagocytosis and protection against PAM can be confirmed in population-based studies, new vaccines could be evaluated for their potential to protect women against PAM by seeing whether the plasma of vaccinees promotes opsonic phagocytosis of CSA-binding PEs.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040181.
US Centers for Disease Control and Prevention information on malaria and malaria during pregnancy (in English and Spanish)
World Health Organization information on malaria, including a feature on malaria in pregnancy (in English, Spanish, French, Arabic, Chinese and Russian)
Special Program for Research and Training in Tropical Diseases (TDR) information on malaria and research into the disease
Roll Back Malaria Partnership fact sheets on all aspects of malaria, including malaria in pregnancy (in English, French and Portuguese)
HIV Insite, information from the University of California at San Francisco on malaria and HIV
doi:10.1371/journal.pmed.0040181
PMCID: PMC1880852  PMID: 17535103
3.  A Population-Based Study on Alcohol and High-Risk Sexual Behaviors in Botswana 
PLoS Medicine  2006;3(10):e392.
Background
In Botswana, an estimated 24% of adults ages 15–49 years are infected with HIV. While alcohol use is strongly associated with HIV infection in Africa, few population-based studies have characterized the association of alcohol use with specific high-risk sexual behaviors.
Methods and Findings
We conducted a cross-sectional, population-based study of 1,268 adults from five districts in Botswana using a stratified two-stage probability sample design. Multivariate logistic regression was used to assess correlates of heavy alcohol consumption (>14 drinks/week for women, and >21 drinks/week for men) as a dependent variable. We also assessed gender-specific associations between alcohol use as a primary independent variable (categorized as none, moderate, problem and heavy drinking) and several risky sex outcomes including: (a) having unprotected sex with a nonmonogamous partner; (b) having multiple sexual partners; and (c) paying for or selling sex in exchange for money or other resources. Criteria for heavy drinking were met by 31% of men and 17% of women. Adjusted correlates of heavy alcohol use included male gender, intergenerational relationships (age gap ≥10 y), higher education, and living with a sexual partner. Among men, heavy alcohol use was associated with higher odds of all risky sex outcomes examined, including unprotected sex (AOR = 3.48; 95% confidence interval [CI], 1.65 to 7.32), multiple partners (AOR = 3.08; 95% CI, 1.95 to 4.87), and paying for sex (AOR = 3.65; 95% CI, 2.58 to 12.37). Similarly, among women, heavy alcohol consumption was associated with higher odds of unprotected sex (AOR = 3.28; 95% CI, 1.71 to 6.28), multiple partners (AOR = 3.05; 95% CI, 1.83 to 5.07), and selling sex (AOR = 8.50; 95% CI, 3.41 to 21.18). A dose-response relationship was seen between alcohol use and risky sexual behaviors, with moderate drinkers at lower risk than both problem and heavy drinkers.
Conclusions
Alcohol use is associated with multiple risks for HIV transmission among both men and women. The findings of this study underscore the need to integrate alcohol abuse and HIV prevention efforts in Botswana and elsewhere.
Alcohol use is associated with multiple risks for HIV transmission in men and women. The findings underscore the need to integrate alcohol abuse and HIV prevention efforts in Botswana and elsewhere.
Editors' Summary
Background.
Human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS), is most commonly spread through unprotected sex with an infected partner. HIV enters the body through the lining of the sex organs, rectum, or mouth, and destroys immune system cells, leaving the infected person susceptible to other viruses and bacteria. Although HIV education and prevention campaigns emphasize the importance of safe sex in reducing HIV transmission, people continue to become infected by having unprotected sex (that is, not using a condom) with either a nonmonogamous partner or multiple sexual partners, or in situations where they are paying for or selling sex. Research in different populations suggested that heavy alcohol use is associated with risky sexual behaviors. This is because alcohol relaxes the brain and body, reduces inhibitions, and diminishes risk perception. Drinking alcohol may further increase the risk of becoming infected with HIV through its suppressive effects on the immune system.
Why Was This Study Done?
Alcohol abuse is widespread in sub-Saharan Africa where most HIV infections occur and has been associated with risky sexual behaviors. It may therefore be one of the most common, potentially modifiable HIV risk factors in this region. However, research to date has concentrated on the association between alcohol consumption and risky sex in people attending HIV-treatment clinics or recruited at beer halls, and these populations may not be representative of the general population of sub-Saharan Africa. In this study, the researchers have investigated the potential role of alcohol in perpetuating the HIV epidemic by undertaking a population-based study on alcohol use and high-risk sexual behaviors in Botswana. Nearly a quarter of adults are infected with HIV here, and alcohol abuse is also common, particularly in the townships.
What Did the Researchers Do and Find?
The researchers recruited a random cross-section of people from the five districts of Botswana with the highest number of HIV-infected individuals and interviewed all 1,268 participants using a questionnaire. This included general questions about the participants (for example, their age and marital status) and questions about alcohol use, sexual behavior, and knowledge of HIV. Overall, 31% of the men in the study and 17% of the women were heavy drinkers—more than 21 drinks/week for men, 14 for women; a drink is half a pint of beer or a glass of wine. Heavy alcohol use was associated with being male, being in an intergenerational relationship (at least 10 years age difference between partners; intergenerational sex facilitates the continued spread of HIV in sub-Saharan Africa), having had more education, and living with a sexual partner. Among men, those who drank heavily were three to four times more likely to have unprotected sex or multiple partners or to pay for sex than nondrinkers. Among women, there was a similar association between heavy drinking and having unprotected sex or multiple partners, and heavy drinkers were eight times as likely to sell sex as nondrinkers. For both men and women, the more they drank, the more likely they were to have risky sex. The study did not address behavior among same-sex partnerships.
What Do These Findings Mean?
This study indicates that heavy alcohol consumption is strongly and consistently associated with sexual risk behaviors in both men and women in Botswana. Because of the study design, it does not prove that heavy alcohol use is the cause of such behaviors but provides strong circumstantial evidence that this is the case. It is possible that these results may not apply to neighboring African countries—Botswana is unique in being relatively wealthy and in its government being strongly committed to tackling HIV. Nevertheless, taken together with the results of other studies, this research strongly argues for the need to deal with alcohol abuse within HIV prevention programs in sub-Saharan Africa. Strategies to do this could include education campaigns that target both alcohol use and HIV in schools and in social venues, including beer halls. But, stress the researchers, any strategy that is used must consider the cultural and social significance of alcohol use (in Botswana, alcohol use is a symbol of masculinity and high socioeconomic status) and must simultaneously tackle not only the overlap between alcohol use and risky sexual behavior but also the overlap between alcohol and other risk behaviors such as intergenerational sex.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030392.
US National Institute of Allergy and Infectious Diseases factsheet on HIV infection and AIDS
US Department of Health and Human Services information on AIDS
US Centers for Disease Control and Prevention information on HIV/AIDS
US National Institute on Alcohol Abuse and Alcoholism patient information on alcohol and HIV/AIDS]
Aidsmap, information on HIV and AIDS provided by the charity NAM,which includes some information on HIV infections and alcohol
AVERT information on HIV and AIDS in Botswana
doi:10.1371/journal.pmed.0030392
PMCID: PMC1592342  PMID: 17032060
4.  HIV, Gender, Race, Sexual Orientation, and Sex Work: A Qualitative Study of Intersectional Stigma Experienced by HIV-Positive Women in Ontario, Canada 
PLoS Medicine  2011;8(11):e1001124.
Mona Loutfy and colleagues used focus groups to examine experiences of stigma and coping strategies among HIV-positive women in Ontario, Canada.
Background
HIV infection rates are increasing among marginalized women in Ontario, Canada. HIV-related stigma, a principal factor contributing to the global HIV epidemic, interacts with structural inequities such as racism, sexism, and homophobia. The study objective was to explore experiences of stigma and coping strategies among HIV-positive women in Ontario, Canada.
Methods and Findings
We conducted a community-based qualitative investigation using focus groups to understand experiences of stigma and discrimination and coping methods among HIV-positive women from marginalized communities. We conducted 15 focus groups with HIV-positive women in five cities across Ontario, Canada. Data were analyzed using thematic analysis to enhance understanding of the lived experiences of diverse HIV-positive women. Focus group participants (n = 104; mean age = 38 years; 69% ethnic minority; 23% lesbian/bisexual; 22% transgender) described stigma/discrimination and coping across micro (intra/interpersonal), meso (social/community), and macro (organizational/political) realms. Participants across focus groups attributed experiences of stigma and discrimination to: HIV-related stigma, sexism and gender discrimination, racism, homophobia and transphobia, and involvement in sex work. Coping strategies included resilience (micro), social networks and support groups (meso), and challenging stigma (macro).
Conclusions
HIV-positive women described interdependent and mutually constitutive relationships between marginalized social identities and inequities such as HIV-related stigma, sexism, racism, and homo/transphobia. These overlapping, multilevel forms of stigma and discrimination are representative of an intersectional model of stigma and discrimination. The present findings also suggest that micro, meso, and macro level factors simultaneously present barriers to health and well being—as well as opportunities for coping—in HIV-positive women's lives. Understanding the deleterious effects of stigma and discrimination on HIV risk, mental health, and access to care among HIV-positive women can inform health care provision, stigma reduction interventions, and public health policy.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
HIV-related stigma and discrimination—prejudice, negative attitudes, abuse, and maltreatment directed at people living with HIV—is a major factor contributing to the global HIV epidemic. HIV-related stigma, which devalues and stereotypes people living with HIV, increases vulnerability to HIV infection by reducing access to HIV prevention, testing, treatment, and support. At the personal (micro) level, HIV-related stigma can make it hard for people to take tests to determine their HIV status or to tell other people that they are HIV positive. At the social/community (meso) level, it can mean that HIV-positive people are ostracized from their communities. At the organizational/political (macro) level, it can mean that health-care workers treat HIV-positive people differently and that governments are deterred from taking fast, effective action against the HIV epidemic. In addition, HIV-related stigma is negatively associated with well-being among people living with HIV. Thus, among HIV-positive people, those who have experienced HIV-related stigma have higher levels of mental and physical illness.
Why Was This Study Done?
Racism (oppression and inequity founded on ethno-racial differences), sexism and gender discrimination (oppression and inequity based on gender bias in attitudes), and homophobia and transphobia (discrimination, fear, hostility, and violence towards nonheterosexual and transgender people, respectively) can also affect access to HIV services. However, little is known about how these different forms of stigma and discrimination interact (intersect). A better understanding of the effect of intersecting stigmas on people living with HIV could help in the development of stigma reduction interventions and HIV prevention, treatment and care programs, and could help to control global HIV infection rates. In this qualitative study (an analysis of people's attitudes and experiences rather than numerical data), the researchers investigate the intersection of HIV-related stigma, racism, sexism and gender discrimination, homophobia and transphobia among marginalized HIV-positive women in Ontario, Canada. As elsewhere in the world, HIV infection rates are increasing among women in Canada. Nearly 25% of people living with HIV in Canada are women and about a quarter of all new infections are in women. Moreover, there is a disproportionately high infection rate among marginalized women in Canada such as sex workers and lesbian, bisexual, and queer women.
What Did the Researchers Do and Find?
The researchers held 15 focus groups with 104 marginalized HIV-positive women who were recruited by word-of-mouth and through flyers circulated in community agencies serving women of diverse ethno-cultural origins. Each focus group explored topics that included challenges in daily life, medical issues and needs, and issues that were silenced within the participants' communities. The researchers analyzed the data from these focus groups using thematic analysis, an approach that identifies, analyzes, and reports themes in qualitative data. They found that women living with HIV in Ontario experienced multiple types of stigma at different levels. So, for example, women experienced HIV-related stigma at the micro (“If you're HIV-positive, you feel shameful”), meso (“The thing I hate most for people that test positive for HIV is that society ostracizes them”), and macro (“A lot of women are not getting employed because they have to disclose their status”) levels. The women also attributed their experiences of stigma and discrimination to sexism and gender discrimination, racism, homophobia and transphobia, and involvement in sex work at all three levels and described coping strategies at the micro (resilience; “I always live with hope”), meso (participation in social networks), and macro (challenging stigma) levels.
What Do These Findings Mean?
These findings indicate that marginalized HIV-positive women living in Ontario experience overlapping forms of stigma and discrimination and that these forms of stigma operate over micro, meso, and macro levels, as do the coping strategies adopted by the women. Together, these results support an intersectional model of stigma and discrimination that should help to inform discussions about the complexity of stigma and coping strategies. However, because only a small sample of nonrandomly selected women was involved in this study, these findings need to be confirmed in other groups of HIV-positive women. If confirmed, the complex system of interplay of different forms of stigma revealed here should help to inform health-care provision, stigma reduction interventions, and public-health policy, and could, ultimately, help to bring the global HIV epidemic under control.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001124.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment; its publication HIV and stigma deals with HIV-related stigma in the UK
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on women, HIV, and AIDS, on HIV and AIDS stigma and discrimination, and on HIV/AIDS statistics for Canada (in English and Spanish)
The People Living with Stigma Index to address stigma relating to HIV and advocate on key barriers and issues perpetuating stigma; it has recently published Piecing it together for women and girls, the gender dimensions of HIV-related stigma; its website will soon include a selection of individual stories about HIV-related stigma
Patient stories about living with HIV/AIDS are available through Avert and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001124
PMCID: PMC3222645  PMID: 22131907
5.  Gender Differences in Survival among Adult Patients Starting Antiretroviral Therapy in South Africa: A Multicentre Cohort Study 
PLoS Medicine  2012;9(9):e1001304.
Morna Cornell and colleagues investigate differences in mortality for HIV-positive men and women on antiretroviral therapy in South Africa.
Background
Increased mortality among men on antiretroviral therapy (ART) has been documented but remains poorly understood. We examined the magnitude of and risk factors for gender differences in mortality on ART.
Methods and Findings
Analyses included 46,201 ART-naïve adults starting ART between January 2002 and December 2009 in eight ART programmes across South Africa (SA). Patients were followed from initiation of ART to outcome or analysis closure. The primary outcome was mortality; secondary outcomes were loss to follow-up (LTF), virologic suppression, and CD4+ cell count responses. Survival analyses were used to examine the hazard of death on ART by gender. Sensitivity analyses were limited to patients who were virologically suppressed and patients whose CD4+ cell count reached >200 cells/µl. We compared gender differences in mortality among HIV+ patients on ART with mortality in an age-standardised HIV-negative population.
Among 46,201 adults (65% female, median age 35 years), during 77,578 person-years of follow-up, men had lower median CD4+ cell counts than women (85 versus 110 cells/µl, p<0.001), were more likely to be classified WHO stage III/IV (86 versus 77%, p<0.001), and had higher mortality in crude (8.5 versus 5.7 deaths/100 person-years, p<0.001) and adjusted analyses (adjusted hazard ratio [AHR] 1.31, 95% CI 1.22–1.41). After 36 months on ART, men were more likely than women to be truly LTF (AHR 1.20, 95% CI 1.12–1.28) but not to die after LTF (AHR 1.04, 95% CI 0.86–1.25). Findings were consistent across all eight programmes. Virologic suppression was similar by gender; women had slightly better immunologic responses than men. Notably, the observed gender differences in mortality on ART were smaller than gender differences in age-standardised death rates in the HIV-negative South African population. Over time, non-HIV mortality appeared to account for an increasing proportion of observed mortality. The analysis was limited by missing data on baseline HIV disease characteristics, and we did not observe directly mortality in HIV-negative populations where the participating cohorts were located.
Conclusions
HIV-infected men have higher mortality on ART than women in South African programmes, but these differences are only partly explained by more advanced HIV disease at the time of ART initiation, differential LTF and subsequent mortality, and differences in responses to treatment. The observed differences in mortality on ART may be best explained by background differences in mortality between men and women in the South African population unrelated to the HIV/AIDS epidemic.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
About 34 million people (most living in low- and middle-income countries) are currently infected with HIV, the virus that causes AIDS. HIV destroys CD4 lymphocytes and other immune system cells, leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within 10 years of becoming infected. Then, in 1996, antiretroviral therapy (ART)—cocktails of drugs that keep HIV in check—became available. For people living in affluent countries, HIV/AIDS became a chronic condition. However, ART was expensive and, for people living in poorer countries, HIV/AIDS remained a fatal illness. In 2003, this situation was declared a global emergency, and governments and international agencies began to implement plans to increase ART coverage in resource-limited countries. Since then, ART programs in these countries have grown rapidly. In South Africa, for example, about 52% of the 3.14 million adults in need of ART were receiving an ART regimen recommended by the World Health Organization by the end of 2010.
Why Was This Study Done?
The outcomes of ART programs in resource-limited countries need to be evaluated thoroughly so that these programs can be optimized. One area of concern to ART providers is that of gender differences in survival among patients receiving treatment. In sub-Saharan Africa, for example, men are more likely to die than women while receiving ART. This gender difference in mortality may arise because men initiating ART in many African ART programs have more advanced HIV disease than women (early ART initiation is associated with better outcomes than late initiation) or because men are more likely to be lost to follow-up than women (failure to continue treatment is associated with death). Other possible explanations for gender differentials in mortality on ART include gender differences in immunologic and virologic responses to treatment (increased numbers of immune system cells and reduced amounts of virus in the blood, respectively). In this multicenter cohort study, the researchers examine the size of, and risk factors for, gender differences in mortality on ART in South Africa by examining data collected from adults starting ART at International Epidemiologic Databases to Evaluate AIDS South Africa (IeDEA-SA) collaboration sites.
What Did the Researchers Do and Find?
The researchers analyzed data collected from 46,201 ART-naïve adults who started ART between 2002 and 2009 in eight IeDEA-SA ART programs. At ART initiation, men had a lower CD4 count on average and were more likely to have advanced HIV disease than women. During the study, after allowing for factors likely to affect mortality such as HIV disease stage at initiation, men on ART had a 31% higher risk of dying than women. Men were more likely to be lost to follow-up than women, but men and women who were lost to follow-up were equally likely to die. Women had a slightly better immunological response to ART than men but virologic suppression was similar in both genders. Importantly, in analyses of mortality limited to individuals who were virologically suppressed at 12 months and to patients who had a good immunological response to ART, men still had a higher risk of death than women. However, the gender differences in mortality on ART were smaller than the gender differences in age-standardized mortality in the HIV-negative South African population.
What Do These Findings Mean?
These analyses show that among South African patients initiating ART between 2002 and 2009, men were more likely to die than women but that this gender difference in mortality on ART cannot be completely explained by gender differences in baseline characteristics, loss to follow-up, or virologic and/or immunologic responses. Instead, the observed gender differences in mortality can best be explained by background gender differences in mortality in the whole South African population. Because substantial amounts of data were missing in this study (for example, HIV disease stage was not available for all the patients), these findings need to be interpreted cautiously. Moreover, similar studies need to be done in other settings to investigate whether they are generalizable to the South African national ART program and to other countries. If confirmed, however, these findings suggest that the root causes of gender differences in mortality on ART may be unrelated to HIV/AIDS or to the characteristics of ART programs.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001304.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
Information on the treatment of HIV/AIDS in South Africa is available from the Southern African HIV Clinicians Society
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 HIV/AIDS treatment and care, and on HIV/AIDS in South Africa (in English and Spanish)
WHO provides information about universal access to AIDS treatment (in several languages); its 2010 ART guidelines can be downloaded
Information about the IeDEA-SA collaboration is available
The Treatment Action Campaign provides information on antiretroviral therapy and South African HIV statistics
Patient stories about living with HIV/AIDS are available through Avert; the nonprofit website Healthtalkonline also provides personal stories about living with HIV, including stories about taking anti-HIV drugs and the challenges of anti-HIV drugs
doi:10.1371/journal.pmed.1001304
PMCID: PMC3433409  PMID: 22973181
6.  Higher serum iron is associated with increased oxidant stress in HIV-infected men 
Journal of acquired immune deficiency syndromes (1999)  2013;64(4):10.1097/QAI.0b013e3182a60f36.
Background
F2-isoprostanes (F2-IsoP) are oxidant stress biomarkers that are higher in HIV-infected women than men. We explored whether the effect of hemoglobin (Hgb), serum iron, or anemia on F2-IsoP is different between HIV-infected women and men.
Methods
Plasma F2-IsoP were quantified by gas chromatography/mass spectrometry; clinical and laboratory data were collected at enrollment or from the medical record. Multivariable linear regression was used to assess associations between F2-IsoP and Hgb, anemia as a dichotomous variable, and serum iron with adjustment for age, sex, race, body-mass index, CD4+ lymphocyte count, self-reported current smoking status, and antiretroviral therapy.
Results
Compared to men, women had lower Hgb (median [IQR] 12.7 [11.8-13.9] vs. 14.9 [13.7-15.8] g/dL, P<0.001), lower iron levels (75 [47-97] vs. 90 [69-121] μg/dL, P=0.004), more anemia (29% vs. 10%, P<0.001), and higher levels of F2-IsoP (42 [32-62] vs. 36 [25-46] pg/mL, P<0.001). The relationship between iron and F2-IsoP differed significantly between men and women (interaction P=0.02). Men had a 21% (95% CI: 8%-36%) increase in F2-IsoP per interquartile increase in iron (P=0.001); while no relationship was seen among women (-4% [-17%-13%], P=0.65).
Conclusions
Although women have overall higher F2-IsoP than men, a relationship between circulating F2-IsoP and iron levels was observed in men but not in women with HIV infection. The association between female sex and higher F2-IsoP is not explained by iron or Hgb levels as the association persists when controlling for these factors. The role of iron in oxidant stress and sex-specific differences among HIV-infected individuals require further study.
doi:10.1097/QAI.0b013e3182a60f36
PMCID: PMC3816092  PMID: 24169121
HIV; isoprostanes; iron; hemoglobin
7.  The Safety of Adult Male Circumcision in HIV-Infected and Uninfected Men in Rakai, Uganda 
PLoS Medicine  2008;5(6):e116.
Background
The objective of the study was to compare rates of adverse events (AEs) related to male circumcision (MC) in HIV-positive and HIV-negative men in order to provide guidance for MC programs that may provide services to HIV-infected and uninfected men.
Methods and Findings
A total of 2,326 HIV-negative and 420 HIV-positive men (World Health Organization [WHO] stage I or II and CD4 counts > 350 cells/mm3) were circumcised in two separate but procedurally identical trials of MC for HIV and/or sexually transmitted infection prevention in rural Rakai, Uganda. Participants were followed at 1–2 d and 5–9 d, and at 4–6 wk, to assess surgery-related AEs, wound healing, and resumption of intercourse. AE risks and wound healing were compared in HIV-positive and HIV-negative men. Adjusted odds ratios (AdjORs) were estimated by multiple logistic regression, adjusting for baseline characteristics and postoperative resumption of sex. At enrollment, HIV-positive men were older, more likely to be married, reported more sexual partners, less condom use, and higher rates of sexually transmitted disease symptoms than HIV-negative men. Risks of moderate or severe AEs were 3.1/100 and 3.5/100 in HIV-positive and HIV-negative participants, respectively (AdjOR 0.91, 95% confidence interval [CI] 0.47–1.74). Infections were the most common AEs (2.6/100 in HIV-positive versus 3.0/100 in HIV-negative men). Risks of other complications were similar in the two groups. The proportion with completed healing by 6 wk postsurgery was 92.7% in HIV-positive men and 95.8% in HIV-negative men (p = 0.007). AEs were more common in men who resumed intercourse before wound healing compared to those who waited (AdjOR 1.56, 95% CI 1.05–2.33).
Conclusions
Overall, the safety of MC was comparable in asymptomatic HIV-positive and HIV-negative men, although healing was somewhat slower among the HIV infected. All men should be strongly counseled to refrain from intercourse until full wound healing is achieved.
Trial registration: http://www.ClinicalTrials.gov; for HIV-negative men, #NCT00047073 and for HIV-positive men, #NCT00047073.
Ron Gray and colleagues report on complications of circumcision in HIV-infected and HIV-uninfected men from two related trials in Uganda, finding increased risk with intercourse before wound healing.
Editors' Summary
Background
Worldwide over 33 million people are thought to be living with HIV, and in the absence of a vaccine, preventing its spread is a major health issue. The World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) estimate that 68% of 2.5 million new infections worldwide in 2007 took place in sub-Saharan Africa, where 76% of 2.1 million AIDS-related deaths also took place.
One of the principal means of person-to-person transmission of HIV is through sex without the protection of a condom. In parts of Africa, male circumcision is performed in infancy or childhood for religious or cultural reasons or is a traditional rite of passage that marks the transition from child to man. Three trials, in South Africa, Kenya, and Uganda, each found that circumcised men were around half as likely as uncircumcised men to contract HIV from HIV-positive female partners. After reviewing the results, WHO and UNAIDS issued joint advice that male circumcision should be promoted for preventing HIV infection in heterosexual men. As male circumcision does not provide complete protection against HIV infection, they advised that it should be promoted in addition to existing strategies of promoting condom use, abstinence, and a reduction in the number of sexual partners.
Why Was This Study Done?
Although earlier studies had shown that adult male circumcision, when performed in Africa under optimal conditions, is a safe procedure for HIV-negative men, it was not known whether it would also be a safe procedure for HIV-positive men. WHO guidelines recommend that HIV-positive men who request the procedure or have a medical need and no contraindications for it should be circumcised. Also, exclusion of HIV-positive men from circumcision programs may result in stigmatization of these men, and discourage participation by men who do not wish to be tested for HIV. Therefore, it is important to know whether the procedure is safe for HIV-positive men.
What Did the Researchers Do and Find?
The authors compared results from two separate clinical trials carried out with identical procedures in rural Rakai, Uganda. The first, which compared the effect of circumcision with no circumcision in HIV-negative men, was one of the three trials that persuaded the WHO and UNAIDS to promote male circumcision as an HIV prevention strategy. The second Rakai trial did the same comparison but in men who were HIV positive and without symptoms. In this present study, the authors used data from both trials to compare the likelihood of surgery-related complications following circumcision for HIV-negative and HIV-positive men.
The trials recruited men aged 15–49, who were randomly assigned to be circumcised either on enrollment or two years later and were followed up to monitor complications related to the procedure, such as infections, as well as wound healing and when the participant first had sex after the operation. Condom use was recorded at enrollment and six months after enrollment.
The researchers found that most complications were infrequent, mild, and comparable in both groups, with moderate-to-severe complications occurring in only 3%–4% of men in each group. However, delayed wound healing was more frequent in HIV-positive men. Complications were more likely among men who had sex before healing was complete; such men were more likely to be HIV-positive and/or married. Similarly, moderate or severe complications were more likely where men had symptoms of sexually transmitted disease at enrollment, although these were treated before surgery, and these men were more likely to be HIV-positive. Six months after enrollment, similar proportions of HIV-positive and HIV-negative men used condoms consistently, but HIV-positive men were more likely to report using condoms inconsistently than HIV-negative men. However, consistent use of a condom increased among the HIV-positive men compared to when they enrolled.
What Do these Findings Mean?
Circumcision in HIV-positive men without symptoms of AIDS has a low rate of complications, although healing is slower than in HIV-negative men. Because of the greater risk of complications if sex is resumed before full healing, both men and their women partners should be advised to have no sex for at least six weeks after the operation. A separately reported analysis from one of these studies found that women partners are more likely to become HIV infected by HIV-positive men who resume sex prior to complete wound healing. Therefore, for protection of both men and their female partners, it is essential to refrain from intercourse after circumcision until the wound has completely healed.
Because the study found no increased risk of surgical complications in HIV-positive men who undergo circumcision, it should not be necessary to screen men with no symptoms of HIV in future circumcision programs. This should reduce the complexity of implementing such programs and reduce any stigma resulting from exclusion, making it likely that more men will be willing to be circumcised. The rise in consistent condom use among HIV-positive men suggests that messages of safe sex are reaching an important target group and changing their behavior, and that circumcision does not make men less likely to use a condom.
The authors also noted that the rates of complications they observed were low compared with those following traditional circumcision procedures. Others have found that circumcision carried out under unsafe conditions has a high rate of complications. The authors of this study comment that the resources and standards of surgery during the trial represented best practice and that to attain similarly low rates of complications—and the confidence of men in the safety of the procedure—there is a need to ensure sufficient resources and high standards of training.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050116.
WHO and the UNAIDS issued a joint report recommending male circumcision for HIV prevention and another on the HIV epidemic worldwide in December 2007
An information pack here on male circumcision and HIV prevention has also been developed jointly by WHO/UNAIDS, the United Nations International Children's Emergency Fund (UNICEF), the United Nations Population Fund (UNFPA), and the World Bank
The University of California San Francisco's HIV InSite provides information on HIV prevention, treatment, and policy
AEGIS is the world's largest searchable database on HIV and AIDS
The National AIDS Trust provides information on HIV prevention
doi:10.1371/journal.pmed.0050116
PMCID: PMC2408615  PMID: 18532873
8.  Are HIV Epidemics among Men Who Have Sex with Men Emerging in the Middle East and North Africa?: A Systematic Review and Data Synthesis 
PLoS Medicine  2011;8(8):e1000444.
A systematic review by Laith Abu-Raddad and colleagues collates and analyzes the epidemiology of HIV among men who have sex with men in Middle Eastern and North African countries.
Background
Men who have sex with men (MSM) bear a disproportionately higher burden of HIV infection than the general population. MSM in the Middle East and North Africa (MENA) are a largely hidden population because of a prevailing stigma towards this type of sexual behavior, thereby limiting the ability to assess infection transmission patterns among them. It is widely perceived that data are virtually nonexistent on MSM and HIV in this region. The objective of this review was to delineate, for the first time, the evidence on the epidemiology of HIV among MSM in MENA.
Methods and Findings
This was a systematic review of all biological, behavioral, and other related data on HIV and MSM in MENA. Sources of data included PubMed (Medline), international organizations' reports and databases, country-level reports and databases including governmental and nongovernmental organization publications, and various other institutional documents. This review showed that onsiderable data are available on MSM and HIV in MENA. While HIV prevalence continues at low levels among different MSM groups, HIV epidemics appear to be emerging in at least few countries, with a prevalence reaching up to 28% among certain MSM groups. By 2008, the contribution of MSM transmission to the total HIV notified cases increased and exceeded 25% in several countries. The high levels of risk behavior (4–14 partners on average in the last six months among different MSM populations) and of biomarkers of risks (such as herpes simplex virus type 2 at 3%–54%), the overall low rate of consistent condom use (generally below 25%), the relative frequency of male sex work (20%–76%), and the substantial overlap with heterosexual risk behavior and injecting drug use suggest potential for further spread.
Conclusions
This systematic review and data synthesis indicate that HIV epidemics appear to be emerging among MSM in at least a few MENA countries and could already be in a concentrated state among several MSM groups. There is an urgent need to expand HIV surveillance and access to HIV testing, prevention, and treatment services in a rapidly narrowing window of opportunity to prevent the worst of HIV transmission among MSM in the Middle East and North Africa.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS first emerged in the early 1980s among gay men living in the US. But, as the disease rapidly spread, it became clear that AIDS also affects heterosexual men and women. Now three decades on, more than 30 million people are infected with HIV, the virus that causes AIDS. HIV is most often spread by having unprotected sex with an infected partner and, globally, most sexual transmission of HIV now occurs during heterosexual sex. However, 5%–10% of all new HIV infections still occur in men who have sex with men (MSM, a term that encompasses homosexual, bisexual, and transgender men, and heterosexual men who sometimes have sex with men). In some countries, male-to-male sexual contact remains the most important transmission route. Moreover, although the global prevalence of HIV infection (the proportion the world's population infected with HIV) has stabilized, the prevalence of HIV infection among MSM seems to be increasing in multiple countries and new and resurgent HIV epidemics among MSM populations are being frequently reported.
Why Was This Study Done?
In the US and the UK, the MSM population is visible and has helped to raise awareness about the risks of HIV transmission through male-to-male sexual contact. In many other countries, MSM are much less visible, fearing discrimination, stigmatization (being considered socially unacceptable) or arrest. In the Middle East and North Africa (MENA, a geographical region that encompasses countries that share historical, socio-cultural, linguistic and religious characteristics), MSM are the most hidden HIV risk group. Consequently, very little is known about HIV transmission patterns among MSM in MENA. Indeed, it is widely thought that there is virtually no information available on the epidemiology (causes, distribution, and control) of HIV among MSM in this region. In this systematic review and data synthesis, the researchers use predefined search criteria to identify all the published and unpublished data on the epidemiology of HIV among MSM in MENA and combine (synthesize) these data to produce a coherent picture of the HIV epidemic in this potentially key group of people for HIV transmission in this region.
What Did the Researchers Do and Find?
The researchers identified 26 articles and 51 other country-level reports and sources of data that included data on the prevalence of male-to-male sexual contact, HIV transmission, levels of high-risk behavior, and the extent of knowledge about HIV among MSM in MENA. The prevalence of HIV infection among MSM was low in most countries but high in others. For example, the infection rate in Pakistan was 27.6% among one MSM group. Importantly, there was some evidence of increasing HIV prevalence and emerging epidemics among MSM in the region. Thus, by 2008, MSM transmission was responsible for more than a quarter of notified cases of HIV in several countries. Worryingly, MSM were involved in several types of HIV-related high risk behavior. For example, they had, on average, between 4 and 14 sexual partners in the past six months, their rates of consistent condom use were generally below 25% and, in some countries, MSM frequently reported injecting drug use, another common mode of HIV transmission. In addition, 20%–75.5% of MSM exchanged sex for money and contact between MSM and female sex workers and other female sexual partners was often common. Finally, although the level of basic knowledge about HIV/AIDS was high, the level of comprehensive knowledge was limited with a high proportion of MSM perceiving their risk of contracting HIV as low.
What Do These Findings Mean?
These findings indicate that there is considerable and increasing data about HIV transmission and risk behavior among MSM in MENA. However, the quality of this evidence varies greatly. Little has been collected over time in individual populations and, because only the visible part of the MSM populations in many MENA countries has been sampled, these findings may not be representative of all MSM in this region. Nevertheless, these findings suggest that HIV epidemics are emerging among MSM in several MENA countries. Importantly, the high levels of risk behaviors practiced by many MSM in MENA mean that MSM could become the pivotal risk group for HIV transmission in this region in the next decade. There is, therefore, an urgent need to expand HIV surveillance and access to HIV testing, prevention and treatment services among MSM in this region to limit the size of the HIV epidemic.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000444.
Information about the status of the HIV epidemic in the Middle East and North Africa can be found in the World Bank/UNAIDS/WHO report Characterizing the HIV/AIDS epidemic in the Middle East and North Africa: Time for strategic action
Information about the global HIV epidemic among men who have sex with men can be found in the World Bank report The Global HIV Epidemics among Men Who Have Sex with Men
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including information on HIV transmission and transmission in gay men and other MSM and on safer sex
Information is available from Avert, an international AIDS charity, on all aspects of HIV/AIDS, including information on HIV, AIDS and men who have sex with men and on HIV and AIDS prevention (in English and Spanish)
The US Centers for Disease Control and Prevention also have information about HIV/AIDS among men who have sex with men (in English and Spanish)
doi:10.1371/journal.pmed.1000444
PMCID: PMC3149074  PMID: 21829329
9.  Life Expectancies of South African Adults Starting Antiretroviral Treatment: Collaborative Analysis of Cohort Studies 
PLoS Medicine  2013;10(4):e1001418.
Leigh Johnson and colleagues estimate the life expectancies of HIV positive South African adults who are taking antiretroviral therapy by using information from 6 programmes between 2001 and 2010.
Background
Few estimates exist of the life expectancy of HIV-positive adults receiving antiretroviral treatment (ART) in low- and middle-income countries. We aimed to estimate the life expectancy of patients starting ART in South Africa and compare it with that of HIV-negative adults.
Methods and Findings
Data were collected from six South African ART cohorts. Analysis was restricted to 37,740 HIV-positive adults starting ART for the first time. Estimates of mortality were obtained by linking patient records to the national population register. Relative survival models were used to estimate the excess mortality attributable to HIV by age, for different baseline CD4 categories and different durations. Non-HIV mortality was estimated using a South African demographic model. The average life expectancy of men starting ART varied between 27.6 y (95% CI: 25.2–30.2) at age 20 y and 10.1 y (95% CI: 9.3–10.8) at age 60 y, while estimates for women at the same ages were substantially higher, at 36.8 y (95% CI: 34.0–39.7) and 14.4 y (95% CI: 13.3–15.3), respectively. The life expectancy of a 20-y-old woman was 43.1 y (95% CI: 40.1–46.0) if her baseline CD4 count was ≥200 cells/µl, compared to 29.5 y (95% CI: 26.2–33.0) if her baseline CD4 count was <50 cells/µl. Life expectancies of patients with baseline CD4 counts ≥200 cells/µl were between 70% and 86% of those in HIV-negative adults of the same age and sex, and life expectancies were increased by 15%–20% in patients who had survived 2 y after starting ART. However, the analysis was limited by a lack of mortality data at longer durations.
Conclusions
South African HIV-positive adults can have a near-normal life expectancy, provided that they start ART before their CD4 count drops below 200 cells/µl. These findings demonstrate that the near-normal life expectancies of HIV-positive individuals receiving ART in high-income countries can apply to low- and middle-income countries as well.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
According to the latest figures, more than 34 million people worldwide currently live with HIV/AIDS. In 2011, an estimated 2.5 million people were newly infected with HIV, and in the same year 1.7 million people died from AIDS. Since the beginning of the epidemic in the 1980s, more than 60 million people have contracted HIV and nearly 30 million have died of HIV-related causes. Despite the stark statistics, the life expectancy for people infected with the AIDS virus has dramatically improved over the past decade since the introduction of an effective combination of antiretroviral drugs. In high-income countries, people who are HIV-positive can expect a near-normal life expectancy if they take these drugs (as antiretroviral treatment—ART) throughout their life.
Why Was This Study Done?
Recent studies investigating the life expectancy of people living with HIV have mostly focused on the situation in high-income settings. The situation in low- and middle-income countries is vastly different. People who are diagnosed with HIV are often late in starting treatment, treatments regimes are sometimes interrupted, and a large proportion of patients are lost to follow-up. It is important to gain a realistic estimate of life expectancy in low- and middle-income countries so patients can be given the best information. So in this study the researchers used a model to estimate the life expectancy of patients starting ART in South Africa, using data from several ART programs.
What Did the Researchers Do and Find?
The researchers used data collected from six programs in South Africa based in Western Cape, Gauteng, and KwaZulu-Natal between 2001 and 2010. The researchers calculated the observation time from the time of ART initiation to the date of death or to the end of the study. Then the researchers used a relative survival approach to model the excess mortality attributable to HIV, relative to non-HIV mortality rates in South Africa, over different periods from ART initiation.
Using these methods, the researchers found that over the time period, 37,740 adults started ART and 2,066 deaths were recorded in patient record systems. Of the 16,250 patients who were lost to follow-up, the researchers identified 2,947 further deaths in the population register. When they inputted these figures into their model, the researchers estimated that the mortality rate was 83.2 per 1,000 person-years of observation (PYO), and was higher in males (99.8 per 1,000 PYO) than in females (72.6 per 1,000 PYO). The researchers also found that the most significant factor determining the life expectancy of treated patients was their age at ART initiation: the average life expectancy of men starting ART varied between 27.6 years at age 20 and 10.1 years at age 60, while corresponding estimates in women were 36.8 and 14.4, respectively. Life expectancies were also significantly influenced by baseline CD4 counts; life expectancies in patients with baseline CD4 counts ≥200 cells/µl were between 70% and 86% of those of HIV-negative adults of the same age and sex, while patients starting ART with CD4 counts of <50 cells/µl had life expectancies that were between 48% and 61% of those of HIV-negative adults. Importantly, the researchers found that life expectancies were also 15%–20% higher in patients who survived their first 24 months after starting ART than in patients of the same age who had just started therapy.
What Do These Findings Mean?
These findings suggest that in South Africa, patients starting ART have life expectancies around 80% of normal life expectancy, provided that they start treatment before their CD4 count drops below 200 cells/µl. Although these results are encouraging, this study highlights that health services must overcome major challenges, such as dealing with late diagnosis, low uptake of CD4 testing, loss from pre-ART care, and delayed ART initiation, if near-normal life expectancies are to be achieved for the majority of HIV-positive South Africans. With the anticipated increase in the fraction of patients starting ART at higher CD4 counts in the future, long-term survival can be expected to increase even further. It is therefore critical that appropriate funding systems and innovative ways to reduce costs are put in place, to ensure the long-term sustainability of ART delivery in low- and middle-income countries.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001418.
The International Epidemiologic Databases to Evaluate AIDS has more statistical information from world regions
amfAR, the Foundation for AIDS Research, works with health care workers and AIDS organizations in developing countries to create and implement effective HIV research, treatment, prevention, and education strategies
doi:10.1371/journal.pmed.1001418
PMCID: PMC3621664  PMID: 23585736
10.  Predicting Patterns of Long-Term CD4 Reconstitution in HIV-Infected Children Starting Antiretroviral Therapy in Sub-Saharan Africa: A Cohort-Based Modelling Study 
PLoS Medicine  2013;10(10):e1001542.
Using data from the ARROW trial, Joanna Lewis and colleagues investigate the CD4 cell count recovery profiles of children infected with HIV starting antiretroviral therapy in Sub-Saharan Africa.
Please see later in the article for the Editors' Summary
Background
Long-term immune reconstitution on antiretroviral therapy (ART) has important implications for HIV-infected children, who increasingly survive into adulthood. Children's response to ART differs from adults', and better descriptive and predictive models of reconstitution are needed to guide policy and direct research. We present statistical models characterising, qualitatively and quantitatively, patterns of long-term CD4 recovery.
Methods and Findings
CD4 counts every 12 wk over a median (interquartile range) of 4.0 (3.7, 4.4) y in 1,206 HIV-infected children, aged 0.4–17.6 y, starting ART in the Antiretroviral Research for Watoto trial (ISRCTN 24791884) were analysed in an exploratory analysis supplementary to the trial's pre-specified outcomes. Most (n = 914; 76%) children's CD4 counts rose quickly on ART to a constant age-corrected level. Using nonlinear mixed-effects models, higher long-term CD4 counts were predicted for children starting ART younger, and with higher CD4 counts (p<0.001). These results suggest that current World Health Organization–recommended CD4 thresholds for starting ART in children ≥5 y will result in lower CD4 counts in older children when they become adults, such that vertically infected children who remain ART-naïve beyond 10 y of age are unlikely ever to normalise CD4 count, regardless of CD4 count at ART initiation. CD4 profiles with four qualitatively distinct reconstitution patterns were seen in the remaining 292 (24%) children. Study limitations included incomplete viral load data, and that the uncertainty in allocating children to distinct reconstitution groups was not modelled.
Conclusions
Although younger ART-naïve children are at high risk of disease progression, they have good potential for achieving high CD4 counts on ART in later life provided ART is initiated following current World Health Organization (WHO), Paediatric European Network for Treatment of AIDS, or US Centers for Disease Control and Prevention guidelines. In contrast, to maximise CD4 reconstitution in treatment-naïve children >10 y, ART should ideally be considered even if there is a low risk of immediate disease progression. Further exploration of the immunological mechanisms for these CD4 recovery profiles should help guide management of paediatric HIV infection and optimise children's immunological development.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, about 3.3 million children under 15 years old are infected with HIV, the virus that causes AIDS. More than 90% of these children live in sub-Saharan Africa, where nearly 600 children become infected with HIV every day, usually acquiring the virus from their mother during pregnancy, birth, or breastfeeding. HIV gradually reduces the numbers of CD4 lymphocytes in the immune system, leaving infected individuals susceptible to other infections. HIV infection can be kept in check but not cured with antiretroviral therapy (ART)—cocktails of drugs that have to be taken every day throughout life. ART reduces the amount of virus in the blood (viral load), which allows the immune system to recover (long-term immune reconstitution). Unfortunately, ART is very expensive, but concerted international efforts over the past decade mean that about a third of children who need ART are now receiving it, including half a million children in sub-Saharan Africa.
Why Was This Study Done?
World Health Organization (WHO) guidelines recommend initiation of ART at age-related CD4 cell count thresholds based on the risk of short-term disease progression. The guidelines recommend that all HIV-positive children under two years old begin ART as soon they receive a diagnosis of HIV infection. For children aged 2–5 years, ART initiation is recommended once the CD4 count drops below 750 cells/µl blood, whereas for older children the threshold for ART initiation is 350 CD4 cells/µl. Because of improved ART coverage, many more HIV-infected children now survive into adulthood than in the past. It is therefore important to know how the timing of ART initiation in childhood affects long-term immune reconstitution. Unfortunately, although several studies have examined the effect of ART on immune reconstitution in adults, the results of these studies cannot be extrapolated to children because of age-related differences in immune reconstitution. In this cohort-based modelling study, the researchers investigate long-term CD4 recovery in a cohort (group) of HIV-infected children initiating ART in Uganda and Zimbabwe, and present statistical models that predict patterns of long-term CD4 status based on age and CD4 count at ART initiation.
What Did the Researchers Do and Find?
To investigate long-term CD4 reconstitution in children, the researchers used CD4 counts collected during the ARROW trial, a study designed to investigate monitoring strategies during first-line ART in 1,206 HIV-positive children. In three-quarters of the children, CD4 reconstitution following ART initiation was asymptotic—CD4 counts increased rapidly immediately after ART initiation, then slowed before eventually reaching a constant level of about 80% of the CD4 count expected in an uninfected child of the same age. Using a nonlinear mixed-effects statistical model that fitted this pattern of immune reconstitution, the researchers predicted CD4 trajectories for children starting ART at different ages and with different CD4 counts. Higher long-term counts were predicted for children starting ART earlier and with higher CD4 counts. Thus, to achieve a CD4 count greater than 700 cells/µl at age 20 years, CD4 counts of at least 96 cells/µl, 130 cells/µl, and 557 cells/µl are needed for children aged two, five, and 12 years, respectively, when they initiate ART. Qualitatively distinct reconstitution patterns were seen in the remaining children in the study.
What Do These Findings Mean?
These findings suggest that young HIV-positive, ART-naïve children can achieve high CD4 counts in later life, provided ART is initiated as recommended in the current WHO guidelines. However, the recommended CD4 count thresholds for ART initiation are unlikely to maximize immune reconstitution in treatment-naïve children over ten years old. Rather, these findings suggest that ART initiation should be considered in these older children when their CD4 count is still high—even though they have a low risk of immediate disease progression—in order to achieve higher long-term CD4 levels. The omission of viral load measurements in the researchers' model may limit the accuracy of these findings. Moreover, although the predictions made by the model apply to children who will go on to experience asymptotic recovery, they are less relevant to those with different recovery profiles, who cannot currently be accurately identified. Further exploration of the immunological mechanisms underlying the CD4 recovery profiles described here should improve our understanding of the factors that determine the response of HIV-positive children to ART and provide information to guide the management of HIV infections in children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001542.
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 HIV and AIDS in Africa and on HIV infection in children (in English and Spanish)
The UNAIDS World AIDS Day Report 2012 provides up-to-date information about the AIDS epidemic and efforts to halt it; the UNAIDS's 2013 Progress Report on the Global Plan provides information on progress towards eliminating new HIV infections among children by 2015
The World Health Organization provides information about universal access to AIDS treatment (in several languages); its 2010 guidelines for ART in infants and children can be downloaded
Information about the ARROW trial is available
Personal stories about living with HIV/AIDS, including stories from young people infected with HIV, are available through Avert, through Nam/aidsmap, and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001542
PMCID: PMC3812080  PMID: 24204216
11.  Inflammatory and Coagulation Biomarkers and Mortality in Patients with HIV Infection 
PLoS Medicine  2008;5(10):e203.
Background
In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]).
We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis.
Methods and Findings
Stored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case–control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 (95% confidence interval [CI], 1.0–4.1; p = 0.05), 8.3 (95% CI, 3.3–20.8; p < 0.0001), and 12.4 (95% CI, 4.2–37.0; p < 0.0001), respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p < 0.0001). In an expanded case–control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8 (95% CI, 1.1–3.1; p = 0.02) to 1.5 (95% CI, 0.8–2.8) and 1.4 (95% CI, 0.8–2.5) after adjustment for latest levels of IL-6 and D-dimer, respectively.
Conclusions
IL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation.
Trial Registration: ClinicalTrials.gov (NCT00027352).
Analyzing biomarker data from participants in a previous randomized controlled trial of continuous versus interrupted HIV treatment (the SMART trial), James Neaton and colleagues find that mortality was related to IL-6 and fibrin D-dimers.
Editors' Summary
Background.
Globally, more than 30 million people are infected with the human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS). HIV infects and destroys immune system cells (including CD4 cells, a type of lymphocyte). The first stage of HIV infection can involve a short flu-like illness but in the second stage, which can last many years, HIV replicates in the lymph glands (small immune system organs throughout the body) without causing any symptoms. Eventually, however, the immune system becomes so damaged that HIV-infected individuals begin to succumb to “opportunistic” infections (for example, bacterial pneumonia) and cancers (in particular, Karposi sarcoma) that the immune system would normally prevent. AIDS itself is characterized by one or more severe opportunistic infections or cancers (so-called AIDS-related diseases) and by a low blood CD4 cell count. HIV infections cannot be cured but antiretroviral therapy (ART)—combinations of powerful antiretroviral drugs—can keep them in check, so many HIV-positive people now have substantially improved life expectancy.
Why Was This Study Done?
Unfortunately, the effectiveness of ART sometimes wanes over time and prolonged ART can cause unpleasant side effects. Consequently, alternative ART regimens are continually being tested in clinical trials. In the Strategies for Management of Anti-Retroviral Therapy (SMART) trial, for example, HIV-positive patients received either continuous ART (the viral suppression or VS arm), or ART only when their CD4 cell counts were below 250 cells/mm3 (the drug conservation or DC arm; the normal adult CD4 cell count is about 1,000 cells/mm3). Unexpectedly, more people died in the DC arm than in the VS arm from non-AIDS diseases (including heart and circulation problems), a result that led to the trial being stopped early. One possible explanation for these excess deaths is that increased HIV levels following ART interruption might have induced an inflammatory response (a non-specific immune response that occurs with infection or wounding) and/or a hypercoagulable state (a condition in which blood clots form inside undamaged blood vessels) and that these changes increased the risk of death from non-AIDS diseases. In this study, the researchers test this hypothesis.
What Did the Researchers Do and Find?
The researchers measured the levels of proteins that indicate the presence of inflammation or increased coagulation (biomarkers) in stored blood samples from the 85 people who died during the SMART trial (55 and 30 of the participants assigned to receive DC and VS, respectively) and from 170 survivors who served as comparison (control) participants. (Two control participants were “matched” to each participant who had died (cases). In this “case-control” study, an increased risk of death was associated with higher levels at study entry of the inflammation biomarkers high-sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6) and of the coagulation biomarker D-dimer. The risk of death among people with hsCRP values in the highest quarter of measured values was twice that among people with hsCRP values in the lowest quarter (this is expressed as an odds ratio of 2). For IL-6 and D-dimer, the equivalent odds ratios were 8.3 and 12.4, respectively. Furthermore, increases in hsCRP, IL-6 and D-dimer after study entry were associated with an increased risk of death. The researchers also measured blood levels of the same biomarkers in 250 randomly chosen patients from each of the two treatment arms. IL-6 levels increased by 30% over the first month of the trial in the DC arm but were unchanged in the VS arm. Over the same period, D-dimer levels increased by 16% and 5% in the DC and VS arms, respectively. Increases in both markers in the DC arm were related to HIV RNA levels after one month.
What Do These Findings Mean?
Taken together, these findings suggest that HIV-induced activation of inflammation and coagulation increases the risk of death among HIV-positive patients and that interrupting ART further increases this risk, possibly by increasing IL-6 and D-dimer levels. Because only a small number of people died in this study, the relationship between these biomarkers and death and illness among treated and untreated HIV-positive individuals needs to be confirmed in further studies. However, these findings suggest that the development of therapies that reduce the effect that HIV replication has on inflammation and blood coagulation, or that reduce IL-6 and D-dimer levels, might extend the life-expectancy of HIV-positive people.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050203.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS and about the SMART trial
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is also available from Avert, an international AIDS charity, on HIV/AIDS
More information about the SMART trial is available on ClinicalTrials.gov, a database of clinical trials maintained by the US National Institutes of Health
doi:10.1371/journal.pmed.0050203
PMCID: PMC2570418  PMID: 18942885
12.  Insulin resistance and adipokines serum levels in a caucasian cohort of hiv-positive patients undergoing antiretroviral therapy: a cross sectional study 
Background
Insulin resistance is frequent in human immunodeficiency virus (HIV) infection and may be related to antiretroviral therapy. Cytokines secreted by adipose tissue (adipokines) are linked to insulin sensitivity. The present study is aimed to assess the prevalence of insulin resistance (IR) and its association with several adipokines, in a non-diabetic Romanian cohort of men and women with HIV-1 infection, undergoing combination antiretroviral therapy (cART).
Methods
A cross-sectional study was conducted in an unselected sample of 89 HIV-1-positive, non-diabetic patients undergoing stable cART for at least 6 months. Metabolic parameters were measured, including fasting plasma insulin, and circulating adiponectin, leptin, resistin, tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) levels. Insulin resistance was estimated by measuring the Quantitative Insulin Sensitivity Check Index (QUICKI), using a cut-off value of 0.33. A linear regression model was fitted to QUICKI to test the association of IR and adipokines levels.
Results
A total of 89 patients (aged 18–65, median: 28 years) including 51 men (57.3%) and 38 women (42.7%) were included in the study. Fifty nine patients (66.3%) were diagnosed with IR based on QUICKI values lower than the cut-off point. IR prevalence was 72.5% in men and 57.6% in women. The presence of the IR was not influenced by either the time of the HIV diagnosis or by the duration of cART. Decreased adiponectin and increased serum triglycerides were associated with increased IR in men (R=0.43, p=0.007). Hyperleptinemia in women was demonstrated to be associated with the presence of IR (R=0.33, p=0.03).
Conclusions
Given the significant prevalence of the IR in our young non-diabetic cohort with HIV infection undergoing antiretroviral therapy reported in our study and the consecutive risk of diabetes and cardiovascular events, we suggest that the IR management should be a central component of HIV-infection therapeutic strategy. As adipokines play major roles in regulating glucose homeostasis with levels varying according to the sex, we suggest that further studies investigating adipokines should base their analyses on gender differences.
doi:10.1186/1472-6823-13-4
PMCID: PMC3562507  PMID: 23351215
Adipokines; Adiponectin; Leptin; Antiretroviral therapy; Insulin resistance; HIV
13.  Towards Universal Voluntary HIV Testing and Counselling: A Systematic Review and Meta-Analysis of Community-Based Approaches 
PLoS Medicine  2013;10(8):e1001496.
In a systematic review and meta-analysis, Amitabh Suthar and colleagues describe the evidence base for different HIV testing and counseling services provided outside of health facilities.
Please see later in the article for the Editors' Summary
Background
Effective national and global HIV responses require a significant expansion of HIV testing and counselling (HTC) to expand access to prevention and care. Facility-based HTC, while essential, is unlikely to meet national and global targets on its own. This article systematically reviews the evidence for community-based HTC.
Methods and Findings
PubMed was searched on 4 March 2013, clinical trial registries were searched on 3 September 2012, and Embase and the World Health Organization Global Index Medicus were searched on 10 April 2012 for studies including community-based HTC (i.e., HTC outside of health facilities). Randomised controlled trials, and observational studies were eligible if they included a community-based testing approach and reported one or more of the following outcomes: uptake, proportion receiving their first HIV test, CD4 value at diagnosis, linkage to care, HIV positivity rate, HTC coverage, HIV incidence, or cost per person tested (outcomes are defined fully in the text). The following community-based HTC approaches were reviewed: (1) door-to-door testing (systematically offering HTC to homes in a catchment area), (2) mobile testing for the general population (offering HTC via a mobile HTC service), (3) index testing (offering HTC to household members of people with HIV and persons who may have been exposed to HIV), (4) mobile testing for men who have sex with men, (5) mobile testing for people who inject drugs, (6) mobile testing for female sex workers, (7) mobile testing for adolescents, (8) self-testing, (9) workplace HTC, (10) church-based HTC, and (11) school-based HTC. The Newcastle-Ottawa Quality Assessment Scale and the Cochrane Collaboration's “risk of bias” tool were used to assess the risk of bias in studies with a comparator arm included in pooled estimates.
 117 studies, including 864,651 participants completing HTC, met the inclusion criteria. The percentage of people offered community-based HTC who accepted HTC was as follows: index testing, 88% of 12,052 participants; self-testing, 87% of 1,839 participants; mobile testing, 87% of 79,475 participants; door-to-door testing, 80% of 555,267 participants; workplace testing, 67% of 62,406 participants; and school-based testing, 62% of 2,593 participants. Mobile HTC uptake among key populations (men who have sex with men, people who inject drugs, female sex workers, and adolescents) ranged from 9% to 100% (among 41,110 participants across studies), with heterogeneity related to how testing was offered. Community-based approaches increased HTC uptake (relative risk [RR] 10.65, 95% confidence interval [CI] 6.27–18.08), the proportion of first-time testers (RR 1.23, 95% CI 1.06–1.42), and the proportion of participants with CD4 counts above 350 cells/µl (RR 1.42, 95% CI 1.16–1.74), and obtained a lower positivity rate (RR 0.59, 95% CI 0.37–0.96), relative to facility-based approaches. 80% (95% CI 75%–85%) of 5,832 community-based HTC participants obtained a CD4 measurement following HIV diagnosis, and 73% (95% CI 61%–85%) of 527 community-based HTC participants initiated antiretroviral therapy following a CD4 measurement indicating eligibility. The data on linking participants without HIV to prevention services were limited. In low- and middle-income countries, the cost per person tested ranged from US$2–US$126. At the population level, community-based HTC increased HTC coverage (RR 7.07, 95% CI 3.52–14.22) and reduced HIV incidence (RR 0.86, 95% CI 0.73–1.02), although the incidence reduction lacked statistical significance. No studies reported any harm arising as a result of having been tested.
Conclusions
Community-based HTC achieved high rates of HTC uptake, reached people with high CD4 counts, and linked people to care. It also obtained a lower HIV positivity rate relative to facility-based approaches. Further research is needed to further improve acceptability of community-based HTC for key populations. HIV programmes should offer community-based HTC linked to prevention and care, in addition to facility-based HTC, to support increased access to HIV prevention, care, and treatment.
Review Registration
International Prospective Register of Systematic Reviews CRD42012002554
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Three decades into the AIDS epidemic, about 34 million people (most living in resource-limited countries) are infected with HIV, the virus that causes AIDS. Every year another 2.2 million people become infected with HIV, usually through unprotected sex with an infected partner, and about 1.7 million people die. Infection with HIV, which gradually destroys the CD4 lymphocytes and other immune system cells that provide protection from life-threatening infections, is usually diagnosed by looking for antibodies to HIV in the blood or saliva. Disease progression is subsequently monitored in HIV-positive individuals by counting the CD4 cells in their blood. Initiation of antiretroviral drug therapy—a combination of drugs that keeps HIV replication in check but that does not cure the infection—is recommended when an individual's CD4 count falls below 500 cells/µl of blood or when he or she develops signs of severe or advanced disease, such as unusual infections.
Why Was This Study Done?
As part of intensified efforts to eliminate HIV/AIDS, United Nations member states recently set several HIV-related targets to be achieved by 2015, including reduced transmission of HIV and increased delivery of antiretroviral therapy. These targets can only be achieved if there is a large expansion in HIV testing and counseling (HTC) and increased access to HIV prevention and care services. The World Health Organization currently recommends that everyone attending a healthcare facility in regions where there is a generalized HIV epidemic (defined as when 1% or more of the general population is HIV-positive) should be offered HTC. However, many people rarely visit healthcare facilities, and others refuse “facility-based” HTC because they fear stigmatization and discrimination. Thus, facility-based HTC alone is unlikely to be sufficient to enable national and global HIV targets to be reached. In this systematic review and meta-analysis, the researchers evaluate the performance of community-based HTC approaches such as index testing (offering HTC to the sexual and injecting partners and household members of people with HIV), mobile testing (offering HTC through a service that visits shopping centers and other public facilities), and door-to-door testing (systematically offering HTC to homes in a catchment area). A systematic review uses predefined criteria to identify all the research on a given topic; meta-analysis combines the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 117 studies (most undertaken in Africa and North America) involving 864,651 participants that evaluated community-based HTC approaches. Among these studies, the percentage of people offered community-based HTC who accepted it (HTC uptake) was 88% for index testing, 87% for self-testing, 80% for door-to-door testing, 67% for workplace testing, and 62% for school-based testing. Compared to facility-based approaches, community-based approaches increased the chances of an individual's CD4 count being above 350 cells/µl at diagnosis (an important observation because early diagnosis improves subsequent outcomes) but had a lower positivity rate, possibly because people with symptoms of HIV are more likely to visit healthcare facilities than healthy individuals. Importantly, 80% of participants in the community-based HTC studies had their CD4 count measured after HIV diagnosis, and 73% of the participants initiated antiretroviral therapy after their CD4 count fell below national eligibility criteria; both these observations suggest that community-based HTC successfully linked people to care. Finally, offering community-based HTC approaches in addition to facility-based approaches increased HTC coverage seven-fold at the population level.
What Do These Findings Mean?
These findings show that community-based HTC can achieve high HTC uptake rates and can reach HIV-positive individuals earlier, when they still have high CD4 counts. Importantly, they also suggest that the level of linkage to care of community-based HTC is similar to that of facility-based HTC. Although the lower positivity rate of community-based HTC approaches means that more people need to be tested with these approaches than with facility-based HTC to identify the same number of HIV-positive individuals, this downside of community-based HTC is likely to be offset by the earlier identification of HIV-positive individuals, which should improve life expectancy and reduce HIV transmission at the population level. Although further studies are needed to evaluate community-based HTC in other regions of the world, these findings suggest that offering community-based HTC in HIV programs in addition to facility-based testing should support the increased access to HIV prevention and care that is required for the intensification of HIV/AIDS elimination efforts.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001496.
The World Health Organization provides information on all aspects of HIV/AIDS, including information on counseling and testing (in several languages)
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 the global HIV/AIDS epidemic, on HIV testing, and on HIV transmission and testing (in English and Spanish)
The UK National Health Service Choices website provides information (including personal stories) about HIV and AIDS
The World AIDS Day Report 2012 provides up-to-date information about the AIDS epidemic and efforts to halt it
Patient stories about living with HIV/AIDS are available through Avert; the nonprofit website Healthtalkonline also provides personal stories about living with HIV, including stories about getting a diagnosis
doi:10.1371/journal.pmed.1001496
PMCID: PMC3742447  PMID: 23966838
14.  An Intervention to Reduce HIV Risk Behavior of Substance-Using Men Who Have Sex with Men: A Two-Group Randomized Trial with a Nonrandomized Third Group 
PLoS Medicine  2010;7(8):e1000329.
In a randomized trial of a behavioral intervention among substance-using men who have sex with men, aimed at reducing sexual risk behavior, Mansergh and colleagues fail to find evidence of a reduction in risk from the intervention.
Background
Substance use during sex is associated with sexual risk behavior among men who have sex with men (MSM), and MSM continue to be the group at highest risk for incident HIV in the United States. The objective of this study is to test the efficacy of a group-based, cognitive-behavioral intervention to reduce risk behavior of substance-using MSM, compared to a randomized attention-control group and a nonrandomized standard HIV-testing group.
Methods and Findings
Participants (n = 1,686) were enrolled in Chicago, Los Angeles, New York City, and San Francisco and randomized to a cognitive-behavioral intervention or attention-control comparison. The nonrandomized group received standard HIV counseling and testing. Intervention group participants received six 2-h group sessions focused on reducing substance use and sexual risk behavior. Attention-control group participants received six 2-h group sessions of videos and discussion of MSM community issues unrelated to substance use, sexual risk, and HIV/AIDS. All three groups received HIV counseling and testing at baseline. The sample reported high-risk behavior during the past 3 mo prior to their baseline visit: 67% reported unprotected anal sex, and 77% reported substance use during their most recent anal sex encounter with a nonprimary partner. The three groups significantly (p<0.05) reduced risk behavior (e.g., unprotected anal sex reduced by 32% at 12-mo follow-up), but were not different (p>0.05) from each other at 3-, 6-, and 12-mo follow-up. Outcomes for the 2-arm comparisons were not significantly different at 12-mo follow-up (e.g., unprotected anal sex, odds ratio = 1.14, confidence interval = 0.86–1.51), nor at earlier time points. Similar results were found for each outcome variable in both 2- and 3-arm comparisons.
Conclusions
These results for reducing sexual risk behavior of substance-using MSM are consistent with results of intervention trials for other populations, which collectively suggest critical challenges for the field of HIV behavioral interventions. Several mechanisms may contribute to statistically indistinguishable reductions in risk outcomes by trial group. More explicit debate is needed in the behavioral intervention field about appropriate scientific designs and methods. As HIV prevention increasingly competes for behavior-change attention alongside other “chronic” diseases and mental health issues, new approaches may better resonate with at-risk groups.
Trial Registration
ClinicalTrials.gov NCT00153361
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS first emerged in the early 1980s among gay men living in the US. As the disease spread around the world, it became clear that AIDS also affects heterosexual men and women. Now, three decades on, more than 30 million people are infected with HIV, the virus that causes AIDS. HIV is most often spread by having unprotected sex with an infected partner and, globally, most sexual transmission of HIV now occurs during heterosexual sex. However, 5%–10% of all new HIV infections still occur in men who have sex with men (MSM, a term that encompasses gay, bisexual, transgendered, and heterosexual men who sometimes have sex with men) and, in several high-income countries, male-to-male sexual contact remains the most important HIV transmission route. In the US, for example, more than half of the approximately 50,000 people who become infected with HIV every year do so through male-to-male sexual contact.
Why Was This Study Done?
In countries where MSM are the group at highest risk of HIV infection, any intervention that reduces HIV transmission in MSM should have a major effect on the overall HIV infection rate. Among MSM, sexual behaviors that increase the risk of HIV infection (for example, not using a condom, having anal sex, having sex with a partner of unknown HIV status, and having sex with many partners) are associated with the use of alcohol and noninjection drugs (for example, inhaled amyl nitrite or poppers) during or shortly before sexual encounters. In this study (Project MIX), the researchers investigate whether a group-based behavioral intervention reduces sexual risk behavior in substance-using MSM.
What Did the Researchers Do and Find?
The researchers recruited substance-using MSM from four US cities who had had risky sex at least once in the past 6 months. Participants were randomized to a cognitive-behavioral intervention or to an attention-control group; a third, nonrandomized group of MSM formed a standard HIV counseling and testing only group. All the groups had HIV counseling and testing at the start of the study and completed a questionnaire about their substance use and sexual risk behavior during their most recent anal sex encounter. The cognitive-behavior group then received six weekly 2-hour group sessions focused on reducing substance use and sexual risk behavior by helping the men change their thinking (cognition) and behavior regarding sexual risk taking. The attention-control group received six group sessions about general MSM issues such as relationships, excluding discussion of substance use, and sexual risk behavior. The participants in both of these groups completed the questionnaire about their substance use and sexual risk behavior again at 3, 6, and 12 months after the group sessions; the participants in the standard HIV counseling and testing group completed the questionnaire again about 5 months after completing the first questionnaire (to control for the time taken by the other two groups to complete the intervention). At baseline, about 67% of the participants reported unprotected anal sex and 77% reported substance use during their most recent anal sex encounter with a nonprimary partner. At the 3-month follow-up, the incidence of sexual risk behavior had fallen to about 43% in all three groups; the incidence of substance use during sex had fallen to about 50%. Risk taking and substance use remained at these levels in the intervention and attention-control groups at the later follow-up time points.
What Do These Findings Mean?
These findings suggest that this cognitive-behavioral intervention is no better at reducing sexual risk taking among substance-using MSM than is an unrelated video-discussion group or standard HIV counseling and testing. One explanation for this negative result might be that brief counseling is especially effective with people who are ready for a change such as MSM willing to enroll in an intervention trial of this type. Alternatively, just being in the trial might have encouraged all the participants to self-report reduced risk behavior. Thus, alternative scientific designs and methods might be needed to find behavioral interventions that can effectively reduce HIV transmission among substance-using MSM and other people at high risk of HIV infection. Importantly, however, these findings raise the question of whether more extensive, multilevel interventions or broader lifestyle and positive health approaches (rather than single-level or single-subject behavioral interventions) might be needed to reduce sexual risk behavior among substance-using MSM.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000329.
Information is available from the US Department of Health and Human Services on HIV prevention programs, research, and policy
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including information on HIV transmission and transmission in gay men and other MSM, on substance abuse and HIV/AIDS, and on safer sex
Information is available from Avert, an international AIDS nonprofit, on all aspects of HIV/AIDS, including information on HIV, AIDS, and men who have sex with men and on drink, drugs, and sex (in English and Spanish)
The US Centers for Disease Control and Prevention also have information for the public and for professionals about HIV/AIDS among men who have sex with men (in English and Spanish)
The US National Institute on Drug Abuse has information on HIV/AIDS and drug abuse, including a resource aimed at educating teenagers about the link between drug abuse and the spread of HIV in the US (in English and Spanish)
doi:10.1371/journal.pmed.1000329
PMCID: PMC2927550  PMID: 20811491
15.  Prevalence of Consensual Male–Male Sex and Sexual Violence, and Associations with HIV in South Africa: A Population-Based Cross-Sectional Study 
PLoS Medicine  2013;10(6):e1001472.
Using a method that offered complete privacy to participants, Rachel Jewkes and colleagues conducted a survey among South African men about their lifetime same-sex experiences.
Please see later in the article for the Editors' Summary
Background
In sub-Saharan Africa the population prevalence of men who have sex with men (MSM) is unknown, as is the population prevalence of male-on-male sexual violence, and whether male-on-male sexual violence may relate to HIV risk. This paper describes lifetime prevalence of consensual male–male sexual behavior and male-on-male sexual violence (victimization and perpetration) in two South African provinces, socio-demographic factors associated with these experiences, and associations with HIV serostatus.
Methods and Findings
In a cross-sectional study conducted in 2008, men aged 18–49 y from randomly selected households in the Eastern Cape and KwaZulu-Natal provinces provided anonymous survey data and dried blood spots for HIV serostatus assessment. Interviews were completed in 1,737 of 2,298 (75.6%) of enumerated and eligible households. From these households, 1,705 men (97.1%) provided data on lifetime history of same-sex experiences, and 1,220 (70.2%) also provided dried blood spots for HIV testing. 5.4% (n = 92) of participants reported a lifetime history of any consensual sexual activity with another man; 9.6% (n = 164) reported any sexual victimization by a man, and 3.0% (n = 51) reported perpetrating sexual violence against another man. 85.0% (n = 79) of men with a history of consensual sex with men reported having a current female partner, and 27.7% (n = 26) reported having a current male partner. Of the latter, 80.6% (n = 21/26) also reported having a female partner. Men reporting a history of consensual male–male sexual behavior are more likely to have been a victim of male-on-male sexual violence (adjusted odds ratio [aOR] = 7.24; 95% CI 4.26–12.3), and to have perpetrated sexual violence against another man (aOR = 3.10; 95% CI 1.22–7.90). Men reporting consensual oral/anal sex with a man were more likely to be HIV+ than men with no such history (aOR = 3.11; 95% CI 1.24–7.80). Men who had raped a man were more likely to be HIV+ than non-perpetrators (aOR = 3.58; 95% CI 1.17–10.9).
Conclusions
In this sample, one in 20 men (5.4%) reported lifetime consensual sexual contact with a man, while about one in ten (9.6%) reported experience of male-on-male sexual violence victimization. Men who reported having had sex with men were more likely to be HIV+, as were men who reported perpetrating sexual violence towards other men. Whilst there was no direct measure of male–female concurrency (having overlapping sexual relationships with men and women), the data suggest that this may have been common. These findings suggest that HIV prevention messages regarding male–male sex in South Africa should be mainstreamed with prevention messages for the general population, and sexual health interventions and HIV prevention interventions for South African men should explicitly address male-on-male sexual violence.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS first emerged in the early 1980s among gay men living in the US, but it soon became clear that AIDS also infects heterosexual men and women. Now, three decades on, globally, 34 million people (two-thirds of whom live in sub-Saharan Africa and half of whom are women) are infected with HIV, the virus that causes AIDS, and 2.5 million people become infected every year. HIV is most often spread by having unprotected sex with an infected partner, and most sexual transmission of HIV now occurs during heterosexual sex. However, 5%–10% of all new HIV infections still occur in men who have sex with men (MSM; homosexual, bisexual, and transgender men, and heterosexual men who sometimes have consensual sex with men). Moreover, in the concentrated HIV epidemics of high-income countries (epidemics in which the prevalence of HIV infection is more than 5% in at-risk populations such as sex workers but less than 1% in the general population), male-to-male sexual contact remains the most important transmission route, and MSM often have a higher prevalence of HIV infection than heterosexual men.
Why Was This Study Done?
By contrast to high-income countries, HIV epidemics in sub-Saharan Africa are generalized—the prevalence of HIV infection is 1% or more in the general population. Because male-to-male sexual behavior is criminalized in many African countries and because homosexuality is widely stigmatized, little is known about the prevalence of consensual male–male sexual behavior in sub-Saharan Africa. This information and a better understanding of male–female sexual concurrency (having overlapping sexual relationships with men and women) and of how male-to-male transmission contributes to generalized HIV epidemics is needed to inform the design of HIV prevention strategies for use in sub-Saharan Africa. In addition, very little is known about male-on-male sexual violence. Such violence is potentially important to study because we know that male-on-female violence is associated with increased HIV risk for both victims and perpetrators. In this cross-sectional study (an investigation that measures population characteristics at a single time point), the researchers use data from a population-based household survey to investigate the lifetime prevalence of consensual male–male sexual behavior and male-on-male sexual violence (victimization and perpetration) among men in South Africa and the association of these experiences with HIV infection.
What Did the Researchers Do and Find?
About 1,700 adult men from randomly selected households in the Eastern Cape and KwaZulu-Natal provinces of South Africa self-completed a survey that included questions about their lifetime history of same-sex experiences using audio-enhanced personal digital assistants, a data collection method that provided a totally private and anonymous environment for the disclosure of illegal and stigmatized behavior; 1,220 of them also provided dried blood spots for HIV testing. Ninety-two men (5.4% of the participants) reported consensual sexual activity (for example, anal or oral sex) with another man at some time during their life; 9.6% of the men reported that they had been forced to have sex with another man (sexual victimization), and 3% reported that they had perpetrated sexual violence against another man. Most of the men who reported consensual sex with men, including those with current male partners, reported that they had a current female partner. Men with a history of consensual male–male sexual behavior were more likely to have been a victim or perpetrator of male-on-male sexual violence than men without a history of such experiences. Finally, men who reported consensual oral or anal sex with a man were more likely to be HIV+ than men without such a history, and perpetrators of male-on-male sexual violence were more likely to be HIV+ than non-perpetrators.
What Do These Findings Mean?
These findings provide new information about male–male sexual behaviors, male-on-male sexual violence, male–female concurrency, and HIV prevalence among men in two South African provinces. The precision of these findings is likely to be affected by the small numbers of men reporting a history of consensual male–male sexual behavior and of male-on-male sexual violence. Importantly, because the study was cross-sectional, these findings cannot indicate whether the association between consensual male–male sexual behaviors and increased risk of male-on-male sexual violence is causal. Moreover, these findings may not be generalizable to other regions of South Africa or to other African countries. Nevertheless, these findings suggest that information about the risks of male–male sexual behaviors should be included in HIV prevention strategies targeted at the general population in South Africa and that HIV prevention interventions for South African men should explicitly address male-on-male sexual violence. Similar HIV prevention strategies may also be suitable for other African countries, but are likely to succeed only in countries that have, like South Africa, decriminalized consensual homosexual behavior.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001472.
This study is further discussed in a PLOS Medicine Perspective by Jerome Singh
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, including 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 HIV and men who have sex with men, on HIV prevention, and on AIDS in Africa (in English and Spanish)
The US Centers for Disease Control and Prevention also has information about HIV/AIDS among men who have sex with men (in English and Spanish)
Patient stories about living with HIV/AIDS are available through Avert; the charity website Healthtalkonline also provides personal stories about living with HIV
doi:10.1371/journal.pmed.1001472
PMCID: PMC3708702  PMID: 23853554
16.  Home-Based Versus Mobile Clinic HIV Testing and Counseling in Rural Lesotho: A Cluster-Randomized Trial 
PLoS Medicine  2014;11(12):e1001768.
Niklaus Labhardt and colleagues investigate how different HIV testing and counseling strategies, based on home visits or mobile clinics, reach different populations in a rural African setting.
Please see later in the article for the Editors' Summary
Background
The success of HIV programs relies on widely accessible HIV testing and counseling (HTC) services at health facilities as well as in the community. Home-based HTC (HB-HTC) is a popular community-based approach to reach persons who do not test at health facilities. Data comparing HB-HTC to other community-based HTC approaches are very limited. This trial compares HB-HTC to mobile clinic HTC (MC-HTC).
Methods and Findings
The trial was powered to test the hypothesis of higher HTC uptake in HB-HTC campaigns than in MC-HTC campaigns. Twelve clusters were randomly allocated to HB-HTC or MC-HTC. The six clusters in the HB-HTC group received 30 1-d multi-disease campaigns (five villages per cluster) that delivered services by going door-to-door, whereas the six clusters in MC-HTC group received campaigns involving community gatherings in the 30 villages with subsequent service provision in mobile clinics. Time allocation and human resources were standardized and equal in both groups. All individuals accessing the campaigns with unknown HIV status or whose last HIV test was >12 wk ago and was negative were eligible. All outcomes were assessed at the individual level. Statistical analysis used multivariable logistic regression. Odds ratios and p-values were adjusted for gender, age, and cluster effect.
Out of 3,197 participants from the 12 clusters, 2,563 (80.2%) were eligible (HB-HTC: 1,171; MC-HTC: 1,392). The results for the primary outcomes were as follows. Overall HTC uptake was higher in the HB-HTC group than in the MC-HTC group (92.5% versus 86.7%; adjusted odds ratio [aOR]: 2.06; 95% CI: 1.18–3.60; p = 0. 011). Among adolescents and adults ≥12 y, HTC uptake did not differ significantly between the two groups; however, in children <12 y, HTC uptake was higher in the HB-HTC arm (87.5% versus 58.7%; aOR: 4.91; 95% CI: 2.41–10.0; p<0.001). Out of those who took up HTC, 114 (4.9%) tested HIV-positive, 39 (3.6%) in the HB-HTC arm and 75 (6.2%) in the MC-HTC arm (aOR: 0.64; 95% CI: 0.48–0.86; p = 0.002). Ten (25.6%) and 19 (25.3%) individuals in the HB-HTC and in the MC-HTC arms, respectively, linked to HIV care within 1 mo after testing positive. Findings for secondary outcomes were as follows: HB-HTC reached more first-time testers, particularly among adolescents and young adults, and had a higher proportion of men among participants. However, after adjusting for clustering, the difference in male participation was not significant anymore.
Age distribution among participants and immunological and clinical stages among persons newly diagnosed HIV-positive did not differ significantly between the two groups. Major study limitations included the campaigns' restriction to weekdays and a relatively low HIV prevalence among participants, the latter indicating that both arms may have reached an underexposed population.
Conclusions
This study demonstrates that both HB-HTC and MC-HTC can achieve high uptake of HTC. The choice between these two community-based strategies will depend on the objective of the activity: HB-HTC was better in reaching children, individuals who had never tested before, and men, while MC-HTC detected more new HIV infections. The low rate of linkage to care after a positive HIV test warrants future consideration of combining community-based HTC approaches with strategies to improve linkage to care for persons who test HIV-positive.
Trial registration
ClinicalTrials.gov NCT01459120
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Annually, about 2.3 million people become newly infected with HIV, the virus that causes AIDS by gradually destroying CD4 cells and other immune system cells, thereby leaving HIV-infected individuals susceptible to other serious infections. HIV can be transmitted through unprotected sex with an infected partner, from an HIV-positive mother to her unborn child, or through the injection of drugs with shared needles. Infection with HIV is usually diagnosed by looking for antibodies to HIV in the blood or saliva. After diagnosis, the progression of HIV infection is monitored by regularly counting the number of CD4 cells in the blood. Initiation of antiretroviral therapy (ART)—a combination of drugs that keeps HIV replication in check but that does not cure the infection—is recommended when an individual's CD4 count falls below 500 cells/µl or when he or she develops signs of advanced or severe disease, such as unusual infections.
Why Was This Study Done?
To control HIV/AIDS, HIV transmission needs to be reduced, and ART delivery needs to be increased. In settings of high HIV prevalence, universal coverage of HIV testing and counseling (HTC) is essential if these goals are to be met. Unfortunately, many people refuse “facility-based” HTC (HTC delivered at health care facilities) because they fear stigmatization and discrimination. Moreover, many people in resource-limited settings rarely visit health care facilities. Community-based HTC may be one way to increase the uptake of HTC, particularly among populations that are hard to reach, such as men and first-time testers, but which form of community-based HTC will be most effective? In this cluster-randomized trial, the researchers ask whether home-based HTC (HB-HTC)—community-based HTC in which health care workers go door-to-door to offer HTC to people in their own home—results in a higher uptake of HTC than HTC delivered through community gatherings and mobile clinics (MC-HTC) in two rural areas in Lesotho. Nearly a quarter of adults are HIV-positive in Lesotho, but only 61% of people who need ART currently receive treatment. A cluster-randomized trial compares outcomes in groups (clusters) of people chosen at random to receive different interventions.
What Did the Researchers Do and Find?
The researchers allocated 12 clusters, each comprising a health center and its catchment area, to the HB-HTC or MC-HTC intervention. In the HB-HTC arm (1,171 participants), HTC teams going door-to-door delivered a multi-disease campaign that included HTC to five villages in each cluster. In the MC-HTC arm (1,392 participants), the multi-disease campaign was delivered at community gatherings with subsequent service provision in mobile clinics. Overall, HTC uptake was higher in the HB-HTC arm than in the MC-HTC arm (92.5% and 86.7% uptake, respectively). Among participants aged ≥12 years, there was no significant difference in HTC uptake between the arms, whereas among children aged <12 years, HTC uptake was significantly higher in the HB-HTC arm than in the MC-HTC arm (87.5% versus 58.7%; a significant difference is a difference unlikely to have happened by chance). Among individuals who took up HTC, 3.6% and 6.2% tested positive for HIV in the HB-HTC arm and MC-HTC arm, respectively. In both arms, only a quarter of individuals who tested positive accessed HIV care within a month of their positive test result. Finally, HB-HTC reached more first-time testers (particularly among adolescents) and tended to reach more men than MC-HTC.
What Do These Findings Mean?
These findings suggest that, in rural Lesotho, both HB-HTC and MC-HTC delivered as part of a multi-disease campaign can achieve a high uptake of HTC. Various aspects of the trial design (for example, the small number of clusters) may limit the accuracy of the findings reported here. Notably, however, these findings suggest that the choice between HB-HTC and MC-HTC should be guided by the objective of the HTC intervention in specific settings. Where equity of access is of concern and where increased HTC coverage, particularly among groups in which HTC coverage is generally poor (including men, first-time testers, and children), is paramount, HB-HTC may be the preferred option. By contrast, the MC-HTC approach may be more appropriate in settings where the detection of new HIV infections is the major goal. Finally, and importantly, the findings of this trial highlight the need for further research into strategies designed to improve the linkage between HIV testing and enrollment into care.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001768.
The World Health Organization provides information on all aspects of HIV/AIDS, including information on HIV counseling and testing (in several languages)
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 the global HIV/AIDS epidemic, on HIV testing, and on HIV/AIDS in Lesotho
The UK National Health Service Choices website provides information (including personal stories) about HIV/AIDS
The “UNAIDS Report on the Global AIDS Epidemic 2013” provides up-to-date information about the AIDS epidemic and efforts to halt it
Stories about living with HIV/AIDS are available through Avert and through healthtalk.org
More information about this trial is available
doi:10.1371/journal.pmed.1001768
PMCID: PMC4267810  PMID: 25513807
17.  GB Virus C (GBV-C) Infection in Hepatitis C Virus (HCV) Seropositive Women with or at Risk for HIV Infection 
PLoS ONE  2014;9(12):e114467.
Background
GB virus C (GBV-C) may have a beneficial impact on HIV disease progression; however, the epidemiologic characteristics of this virus are not well characterized. Behavioral factors and gender may lead to differential rates of GBV-C infection; yet, studies have rarely addressed GBV-C infections in women or racial/ethnic minorities. Therefore, we evaluated GBV-C RNA prevalence and genotype distribution in a large prospective study of high-risk women in the US.
Results
438 hepatitis C virus (HCV) seropositive women, including 306 HIV-infected and 132 HIV-uninfected women, from the HIV Epidemiologic Research Study were evaluated for GBV-C RNA. 347 (79.2%) women were GBV-C RNA negative, while 91 (20.8%) were GBV-C RNA positive. GBV-C positive women were younger than GBV-C negative women. Among 306 HIV-infected women, 70 (22.9%) women were HIV/GBV-C co-infected. Among HIV-infected women, the only significant difference between GBV-negative and GBV-positive women was age (mean 38.4 vs. 35.1 years; p<0.001). Median baseline CD4 cell counts and plasma HIV RNA levels were similar. The GBV-C genotypes were 1 (n = 31; 44.3%), 2 (n = 36; 51.4%), and 3 (n = 3; 4.3%). The distribution of GBV-C genotypes in co-infected women differed significantly by race/ethnicity. However, median CD4 cell counts and log10 HIV RNA levels did not differ by GBV-C genotype. GBV-C incidence was 2.7% over a median follow-up of 2.9 (IQR: 1.5, 4.9) years, while GBV-C clearance was 35.7% over a median follow-up of 2.44 (1.4, 3.5) years. 4 women switched genotypes.
Conclusions
Age, injection drug use, a history of sex for money or drugs, and number of recent male sex partners were associated with GBV-C infection among all women in this analysis. However, CD4 cell count and HIV viral load of HIV/HCV/GBV-C co-infected women were not different although race was associated with GBV-C genotype.
doi:10.1371/journal.pone.0114467
PMCID: PMC4262414  PMID: 25493916
18.  Sex Disparities in Overall Burden of Disease Among HIV-Infected Individuals in the Veterans Affairs Healthcare System 
Journal of General Internal Medicine  2013;28(Suppl 2):577-582.
ABSTRACT
BACKGROUND
Whether sex disparities exist in overall burden of disease among human immunodeficiency virus (HIV)-infected individuals in the Veterans Affairs healthcare system (VA) is unknown.
OBJECTIVE
To determine whether sex differences exist in overall burden of disease after 1 year of combined antiretroviral therapy (ART) among HIV-infected individuals in VA.
DESIGN
Retrospective cohort study.
PARTICIPANTS
Among patients in the Veterans Aging Cohort Study Virtual Cohort (VACS-VC), all ART-naïve HIV-infected Veterans who received VA-based HIV care between 1996 and 2009.
MAIN MEASURES
Overall burden of disease was measured using the VACS Index, an index that incorporates HIV (e.g. CD4 cell count) and non-HIV biomarkers (e.g. hemoglobin) and is highly predictive of all-cause mortality. Possible scores range from 0 to 164, although scores typically range from 0 to 50 for 80 % of patients in VACS-VC. A higher score indicates greater burden of disease (each additional five points indicates approximately 20 % increased 5-year mortality risk). ART adherence was measured using pharmacy data.
KEY RESULTS
Complete data were available for 227 women and 8,073 men. At ART initiation, compared with men, women were younger and more likely to be Black, less likely to have liver dysfunction, but more likely to have lower hemoglobin levels. Median VACS Index scores changed from ART initiation to 1 year after ART initiation: women’s scores went from 41 to 28 for women (13 point improvement) and men’s from 42 to 27 for men (15 point improvement). In multivariable regression, women had 3.6 point worse scores than men after 1 year on ART (p = 0.002); this difference decreased to 3.2 points after adjusting for adherence (p = 0.004).
CONCLUSIONS
In VA, compared to men, women experienced less improvement in overall burden of disease after 1 year of HIV treatment. Further study is needed to elucidate the modifiable factors that may explain this disparity.
doi:10.1007/s11606-013-2346-z
PMCID: PMC3695278  PMID: 23807068
women; Veterans; HIV; health care disparities; burden of illness
19.  Nevirapine- Versus Lopinavir/Ritonavir-Based Initial Therapy for HIV-1 Infection among Women in Africa: A Randomized Trial 
PLoS Medicine  2012;9(6):e1001236.
In a randomized control trial, Shahin Lockman and colleagues compare nevirapine-based therapy with lopinavir/ritonavir-based therapy for HIV-infected women without previous exposure to antiretroviral treatment.
Background
Nevirapine (NVP) is widely used in antiretroviral treatment (ART) of HIV-1 globally. The primary objective of the AA5208/OCTANE trial was to compare the efficacy of NVP-based versus lopinavir/ritonavir (LPV/r)-based initial ART.
Methods and Findings
In seven African countries (Botswana, Kenya, Malawi, South Africa, Uganda, Zambia, and Zimbabwe), 500 antiretroviral-naïve HIV-infected women with CD4<200 cells/mm3 were enrolled into a two-arm randomized trial to initiate open-label ART with tenofovir (TDF)/emtricitabine (FTC) once/day plus either NVP (n = 249) or LPV/r (n = 251) twice/day, and followed for ≥48 weeks. The primary endpoint was time from randomization to death or confirmed virologic failure ([VF]) (plasma HIV RNA<1 log10 below baseline 12 weeks after treatment initiation, or ≥400 copies/ml at or after 24 weeks), with comparison between treatments based on hazard ratios (HRs) in intention-to-treat analysis. Equivalence of randomized treatments was defined as finding the 95% CI for HR for virological failure or death in the range 0.5 to 2.0. Baseline characteristics were (median): age = 34 years, CD4 = 121 cells/mm3, HIV RNA = 5.2 log10copies/ml. Median follow-up = 118 weeks; 29 (6%) women were lost to follow-up. 42 women (37 VFs, five deaths; 17%) in the NVP and 50 (43 VFs, seven deaths; 20%) in the LPV/r arm reached the primary endpoint (HR 0.85, 95% CI 0.56–1.29). During initial assigned treatment, 14% and 16% of women receiving NVP and LPV/r experienced grade 3/4 signs/symptoms and 26% and 22% experienced grade 3/4 laboratory abnormalities. However, 35 (14%) women discontinued NVP because of adverse events, most in the first 8 weeks, versus none for LPV/r (p<0.001). VF, death, or permanent treatment discontinuation occurred in 80 (32%) of NVP and 54 (22%) of LPV/r arms (HR = 1.7, 95% CI 1.2–2.4), with the difference primarily due to more treatment discontinuation in the NVP arm. 13 (45%) of 29 women tested in the NVP versus six (15%) of 40 in the LPV/r arm had any drug resistance mutation at time of VF.
Conclusions
Initial ART with NVP+TDF/FTC demonstrated equivalent virologic efficacy but higher rates of treatment discontinuation and new drug resistance compared with LPV/r+TDF/FTC in antiretroviral-naïve women with CD4<200 cells/mm3.
Trial registration
ClinicalTrials.gov NCT00089505
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 34 million people (mostly living in low- or middle-income countries) are currently infected with HIV, the virus that causes AIDS. HIV destroys CD4 lymphocytes and other immune cells, leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within 10 years of infection. Then, in 1996, antiretroviral therapy (ART)—cocktails of drugs that attack different parts of HIV—became available. For people living in affluent countries, HIV/AIDS became a chronic condition. But, because ART was expensive, for people living in developing countries, HIV/AIDS remained a fatal illness. In 2006, the international community set a target of achieving universal access to ART by 2010 and, although this target has not been reached, by the end of 2010, 6.6 million of the estimated 15 million people in need of ART in developing countries were receiving one of the ART regimens recommended by the World Health Organization (WHO) in its 2010 guidelines.
Why Was This Study Done?
A widely used combination for the initial treatment of HIV-infected people (particularly women) in resource-limited settings is tenofovir and emtricitabine (both nucleotide reverse transcriptase inhibitors; reverse transcriptase is essential for HIV replication) and nevirapine (NVP, a non-nucleoside reverse transcriptase inhibitor). However, little is known about the efficacy of this NVP-based ART combination. Moreover, its efficacy and toxicity has not been compared with regimens containing lopinavir/ritonavir (LPV/r). LPV/r, which inhibits the viral protease that is essential for HIV replication, is available in resource-limited settings but is usually reserved for second-line treatment. LPV/r-based ART is more expensive than NVP-based ART but if it were more effective or better tolerated than NVP-based ART, then first-line treatment with LPV/r-based ART might be cost-effective in resource-limited settings. Conversely, evidence of the clinical equivalence of NVP-based and LPV/r-based ART would provide support for NVP-based ART as an initial therapy. In this randomized equivalence trial, the researchers compare the efficacy and toxicity of NVP-based and LVP/r-based initial therapy for HIV infection among antiretroviral-naïve African women. In a randomized trial, patients are assigned different treatments by the play of chance and followed to compare the effects of these treatments; an equivalence trial asks whether the effects of two treatments are statistically equivalent.
What Did the Researchers Do and Find?
The researchers followed 500 antiretroviral-naïve HIV-infected women with a low CD4 cell count living in seven African countries, half of whom received NVP-based ART and half of whom received LPV/r-based ART, for an average of 118 weeks and recorded the time to virologic failure (the presence of virus in the blood above pre-specified levels) or death among the participants. Forty-two women in the NVP arm reached this primary endpoint (37 virologic failures and five deaths) compared to 50 women in the LPV/r arm (43 virologic failures and seven deaths), a result that indicates equivalent virologic efficacy according to preset statistical criteria. During the initial assigned treatment, similar proportions of women in both treatment arms developed serious drug-related signs and symptoms and laboratory abnormalities. However, whereas 14% of the women in the NVP arm discontinued treatment because of adverse effects, none of the women in the LPV/r arm discontinued treatment. Finally, nearly half of the women tested in the NVP arm but only 15% of the women tested in the LVP/r arm had developed any drug resistance at the time of virologic failure.
What Do These Findings Mean?
These findings indicate that, among HIV-infected, treatment-naïve African women, initial NVP-based ART is as effective as LPV/r-based ART in terms of virologic failure and death although more women in the NVP arm discontinued treatment or developed new drug resistance than in the LPV/r arm. Several limitations of this study may affect the accuracy of these findings. In particular, some of the study participants may have been exposed to single-dose NVP during childbirth to prevent mother-to-child transmission of HIV; in a parallel randomized trial, the researchers found that LPV/r-based ART was superior to NVP-based ART among women with prior exposure to single-dose NVP. Moreover, the duration of the current study means the long-term effects of the two treatments cannot be compared. Nevertheless, these findings support the WHO recommendation of NVP-based ART with careful early toxicity monitoring as an initial affordable and effective HIV treatment regiment in resource-limited settings, until access to better-tolerated and more potent regimens is possible.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001236.
Information is available from the US National Institute of Allergy and Infectious Diseases on all aspects of HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment (in several languages)
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including detailed information on HIV treatment and care (in English and Spanish)
WHO provides information about universal access to AIDS treatment (in English, French and Spanish); its 2010 ART guidelines can be downloaded
More information about this trial, the OCTANE trial, is available
MedlinePlus provides detailed information about nevirapine and lopinavir/ritinovir (in English and Spanish)
Patient stories about living with HIV/AIDS are available through Avert; the nonprofit website Healthtalkonline also provides personal stories about living with HIV, including stories about taking anti-HIV drugs and the challenges of anti-HIV drugs
doi:10.1371/journal.pmed.1001236
PMCID: PMC3373629  PMID: 22719231
20.  Elevated Risk for HIV Infection among Men Who Have Sex with Men in Low- and Middle-Income Countries 2000–2006: A Systematic Review 
PLoS Medicine  2007;4(12):e339.
Background
Recent reports of high HIV infection rates among men who have sex with men (MSM) from Asia, Africa, Latin America, and the former Soviet Union (FSU) suggest high levels of HIV transmission among MSM in low- and middle-income countries. To investigate the global epidemic of HIV among MSM and the relationship of MSM outbreaks to general populations, we conducted a comprehensive review of HIV studies among MSM in low- and middle-income countries and performed a meta-analysis of reported MSM and reproductive-age adult HIV prevalence data.
Methods and Findings
A comprehensive review of the literature was conducted using systematic methodology. Data regarding HIV prevalence and total sample size was sequestered from each of the studies that met inclusion criteria and aggregate values for each country were calculated. Pooled odds ratio (OR) estimates were stratified by factors including HIV prevalence of the country, Joint United Nations Programme on HIV/AIDS (UNAIDS)–classified level of HIV epidemic, geographic region, and whether or not injection drug users (IDUs) played a significant role in given epidemic. Pooled ORs were stratified by prevalence level; very low-prevalence countries had an overall MSM OR of 58.4 (95% CI 56.3–60.6); low-prevalence countries, 14.4 (95% CI 13.8–14.9); and medium- to high-prevalence countries, 9.6 (95% CI 9.0–10.2). Significant differences in ORs for HIV infection among MSM in were seen when comparing low- and middle-income countries; low-income countries had an OR of 7.8 (95% CI 7.2–8.4), whereas middle-income countries had an OR of 23.4 (95% CI 22.8–24.0). Stratifying the pooled ORs by whether the country had a substantial component of IDU spread resulted in an OR of 12.8 (95% CI 12.3–13.4) in countries where IDU transmission was prevalent, and 24.4 (95% CI 23.7–25.2) where it was not. By region, the OR for MSM in the Americas was 33.3 (95% CI 32.3–34.2); 18.7 (95% CI 17.7–19.7) for Asia; 3.8 (95% CI 3.3–4.3) for Africa; and 1.3 (95% CI 1.1–1.6) for the low- and middle-income countries of Europe.
Conclusions
MSM have a markedly greater risk of being infected with HIV compared with general population samples from low- and middle-income countries in the Americas, Asia, and Africa. ORs for HIV infection in MSM are elevated across prevalence levels by country and decrease as general population prevalence increases, but remain 9-fold higher in medium–high prevalence settings. MSM from low- and middle-income countries are in urgent need of prevention and care, and appear to be both understudied and underserved.
From a systematic review, Chris Beyrer and colleagues conclude that men who have sex with men in the Americas, Asia, and Africa have a markedly greater risk of being HIV-infected than does the general population.
Editors' Summary
Background.
AIDS (acquired immunodeficiency syndrome) first emerged in the early 1980s among gay men living in New York and California. But, as the disease rapidly spread around the world, it became clear that AIDS also affected heterosexual men and women. Now, a quarter of a century later, 40 million people are infected with human immunodeficiency virus (HIV), the organism that causes AIDS. HIV is most often spread by having unprotected sex with an infected partner and in sub-Saharan Africa, the region most badly hit by HIV/AIDS, heterosexual transmission predominates. However, globally, 5%–10% of all HIV infections are thought to be in men who have sex with men (MSM, a term that encompasses gay, bisexual, transgendered, and heterosexual men who sometimes have sex with men), and in several high-income countries, including the US, male-to-male sexual contact remains the most important HIV transmission route.
Why Was This Study Done?
In the US, the MSM population is visible and there is considerable awareness about the risks of HIV transmission associated with sex between men. In many other countries, MSM are much less visible. They remain invisible because they fear discrimination, stigmatization (being considered socially unacceptable), or arrest—sex between men is illegal in 85 countries. Consequently, MSM are often under-represented in HIV surveillance systems and in prevention and care programs. If the AIDS epidemic is going to be halted, much more needs to be known about HIV prevalence (the proportion of the population that is infected) among MSM. In this study, the researchers have done a systematic review (a type of research where the results of existing studies are brought together) on published reports of HIV prevalence among MSM in low- and middle-income countries to get a better picture of the global epidemic of HIV in this population.
What Did the Researchers Do and Find?
The researchers found 83 published studies that reported HIV prevalence in 38 low- and middle-income countries in Asia, Africa, the Americas, and Eastern Europe. When the results were pooled—in what statisticians call a meta-analysis—MSM were found to have a 19.3-times greater chance of being infected with HIV than the general population. This is described as a pooled odds ratio (OR) of 19.3. The researchers also did several subgroup analyses where they asked whether factors such as injection drug use (another risk factor for HIV transmission), per capita income, geographical region, or the HIV prevalence in the general population were associated with differential risk (increase in odds) of HIV infection compared to the general population. They found, for example, that in countries where the prevalence of HIV in the general population was very low (less than 1 adult in 1,000 infected) the pooled OR for MSM compared to the general population was 58.4; where it was high (more than 1 adult in 20 infected), the pooled OR for MSM was 9.6.
What Do These Findings Mean?
These findings indicate that MSM living in low- to middle-income countries have a greater risk of HIV infection than the general populations of these countries. The subgroup analyses indicate that the high HIV prevalence among MSM is not limited to any one region or income level or to countries with any specific HIV prevalence or injection drug use level. Although the small number and design of the studies included in the meta-analysis may affect the numerical accuracy of these findings, the clear trend toward a higher HIV prevalence of among MSM suggests that HIV surveillance efforts should be expanded to include MSM in those countries where they are currently ignored. Efforts should also be made to include MSM in HIV prevention programs and to improve the efficacy of these programs by investigating the cultural, behavioral, social, and public policy factors that underlie the high HIV prevalence among MSM. By increasing surveillance, research, and prevention among MSM in low- to middle-income countries, it should be possible to curb HIV transmission in this marginalized population and reduce the global burden of HIV.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040339.
The International Lesbian and Gay Association provides a world legal map on legislation affecting lesbian, gay, bisexual, and transgendered people
The International Gay and Lesbian Human Rights Commission provides a page called Off the Map: How HIV/AIDS Programming is Failing Same-Sex Practicing People in Africa
The American Foundation for AIDS Research (amfAR) has launched their MSM initiative, which is focused on providing support to front-line community groups working on providing services and doing research focused on HIV among MSM in lower income-settings
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including a list of organizations that provide information for gay men and MSM
Information is available from Avert, an international AIDS charity, on HIV, AIDS, and men who have sex with men
The US Centers for Disease Control and Prevention provides information on HIV/AIDS and on HIV/AIDS among men who have sex with men (in English and Spanish)
doi:10.1371/journal.pmed.0040339
PMCID: PMC2100144  PMID: 18052602
21.  Early and Late Direct Costs in a Southern African Antiretroviral Treatment Programme: A Retrospective Cohort Analysis 
PLoS Medicine  2009;6(12):e1000189.
Gary Maartens and colleagues describe the direct heath care costs and identify the drivers of cost over time in an HIV managed care program in Southern Africa.
Background
There is a paucity of data on the health care costs of antiretroviral therapy (ART) programmes in Africa. Our objectives were to describe the direct heath care costs and establish the cost drivers over time in an HIV managed care programme in Southern Africa.
Methods/Findings
We analysed the direct costs of treating HIV-infected adults enrolled in the managed care programme from 3 years before starting non-nucleoside reverse transcriptase inhibitor-based ART up to 5 years afterwards. The CD4 cell count criterion for starting ART was <350 cells/µl. We explored associations between variables and mean total costs over time using a generalised linear model with a log-link function and a gamma distribution. Our cohort consisted of 10,735 patients (59.4% women) with 594,497 mo of follow up data (50.9% of months on ART). Median baseline CD4+ cell count and viral load were 125 cells/µl and 5.16 log10 copies/ml respectively. There was a peak in costs in the period around ART initiation (from 4 mo before until 4 mo after starting ART) driven largely by hospitalisation, following which costs plateaued for 5 years. The variables associated with changes in mean total costs varied with time. Key early associations with higher costs were low baseline CD4+ cell count, high baseline HIV viral load, and shorter duration in HIV care prior to starting ART; whilst later associations with higher costs were lower ART adherence, switching to protease inhibitor-based ART, and starting ART at an older age.
Conclusions
Drivers of mean total costs changed considerably over time. Starting ART at higher CD4 counts or longer pre-ART care should reduce early costs. Monitoring ART adherence and interventions to improve it should reduce later costs. Cost models of ART should take into account these time-dependent cost drivers, and include costs before starting ART.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 30 million people (22 million people in sub-Saharan Africa alone) are infected with the human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS). HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, on average HIV-positive people died within 10 years of infection. Then, in 1996, highly active antiretroviral therapy (ART; combinations of powerful antiretroviral drugs) was developed. For people living in affluent, developed countries HIV/AIDS became a chronic, treatable condition, but for the millions of HIV-infected people living in low- and middle-income countries, effective treatment was unavailable and HIV/AIDS remained a fatal illness. In 2003, this situation was declared a global health emergency and governments, international agencies, and funding bodies began to implement plans to increase ART coverage in developing countries. By the end of 2008, of the 9.5 million people in need of ART in low- and middle-income countries, more than 4 million people were receiving treatment.
Why Was This Study Done?
Good progress is being made towards achieving universal access to ART, partly because the cost of antiretroviral drugs has plummeted in developing countries. But the provision of antiretroviral drugs is not the only direct cost associated with ART. General practitioner, specialist, and maternity-related care for patients receiving ART, hospital accommodation when necessary, and the investigations that are needed to monitor the progress of HIV infection such as CD4 cell counts and viral load measurements all incur considerable costs. To use their limited resources effectively, public-health officials in developing countries need to know as much as possible about the direct costs of HIV health care but few studies have investigated these costs, particularly those incurred before an individual starts taking ART. In this study, the researchers explore health care costs in a South African private-sector HIV/AIDS program and examine the variables that drive the costs of HIV health care around the time of ART initiation and during later phases of ART.
What Did the Researchers Do and Find?
The researchers analyzed the direct costs of treating more than 100,000 HIV-infected adults enrolled in a private HIV care program in South Africa from 3 years before they started ART until up to 5 years after ART initiation; within this program, individuals began to receive ART when their CD4 cell count fell below 350 cells/µl of blood. The researchers found a peak in direct health costs from 4 months before to 4 months after starting ART (the “peri-ART” period), which was driven mainly by hospital costs. After the peri-ART period, costs dropped (although not to the levels seen before this period) and stabilized at an intermediate level for the next 5 years. Detailed statistical analyses suggest that the key variables associated with higher costs in the peri-ART period were a low baseline CD4 cell count, a high baseline HIV viral load, and a shorter time in HIV care before ART initiation. The key variable associated with higher costs later in ART was lower adherence to the drug therapy. That is, costs were higher among patients who did not take their antiretroviral drugs regularly.
What Do These Findings Mean?
This study involved patients enrolled in a private health care program in which the criteria for initiating ART differed somewhat from those recommended by the World Health Organization for ART initiation in resource-limited settings. Thus, the absolute mean total costs calculated by the researchers are unlikely to be generalizable to public HIV care systems in South Africa and in other resource-poor settings. However, the finding that the drivers of mean total costs change considerably over time may be generalizable and provides some useful information for public-health planners that can now be tested in other, more resource-limited patient populations. In particular, the findings of this study suggest that the high early costs of ART programs could be reduced by starting ART at higher CD4 cell counts or by providing longer pre-ART care. In addition, the findings suggest that monitoring ART adherence and introducing interventions to improve ART adherence could reduce the later direct costs of ART programs.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000189.
Information is available from the US National Institute of Allergy and infectious diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on the HIV and AIDS in Africa, and on universal access to AIDS treatment (in English and Spanish)
The World Health Organization provides information about universal access to AIDS treatment, including the September 2009 progress report (in English and French)
The US Centers for Disease Control and Prevention also provides information on global efforts to deal with the HIV/AIDS epidemic
doi:10.1371/journal.pmed.1000189
PMCID: PMC2777319  PMID: 19956658
22.  Vitamin D deficiency in HIV-infected postmenopausal Hispanic and African-American women 
Summary
We evaluated vitamin D status in HIV+ and HIV− postmenopausal African-American (AA) and Hispanic women. Most women (74–78%) had insufficient 25-hydroxyvitamin D (25OHD) levels, regardless of HIV status. 25OHD was lower in AA women and women lacking supplement use, providing support for screening and supplementation. Among HIV+ women, 25OHD was associated with current CD4 but not type of antiretroviral therapy.
Introduction
To evaluate vitamin D status and factors associated with vitamin D deficiency and insufficiency in HIV-infected (HIV+) postmenopausal minority women.
Methods
In this cross-sectional study, 89 HIV+ and 95 HIV− postmenopausal women (33% AA and 67% Hispanic) underwent assessment of 25OHD, 1,25-dihydroxyvitamin D, parathyroid hormone, markers of bone turnover and bone mineral density by dual energy X-ray absorptiometry.
Results
The prevalence of low 25OHD did not differ by HIV status; the majority of both HIV+ and HIV− women (74–78%) had insufficient levels (<30 ng/ml). Regardless of HIV status, 25OHD was significantly lower in AA subjects, and higher in subjects who used both calcium and multi-vitamins. In HIV+ women on antiretroviral therapy (ART), 25OHD was directly associated with current CD4 count (r= 0.32; p<0.01) independent of age, ethnicity, BMI, or history of AIDS-defining illness. No association was observed between 1,25(OH)2D and CD4 count or between serum 25OHD, 1,25(OH)2D or PTH and type of ART.
Conclusions
In postmenopausal minority women, vitamin D deficiency was highly prevalent and associated with AA race and lack of supplement use, as well as lower current CD4 cell count. These results provide support for screening and repletion of vitamin D in HIV+ patients.
doi:10.1007/s00198-010-1299-x
PMCID: PMC3105902  PMID: 20585939
African-American; Hispanic; HIV+ postmenopausal women; Vitamin D
23.  Comparative gender analysis of the efficacy and safety of atazanavir/ritonavir and lopinavir/ritonavir at 96 weeks in the CASTLE study 
Objectives
To examine whether the overall results of the CASTLE study pertain to both genders, we analysed the efficacy and safety of atazanavir/ritonavir and lopinavir/ritonavir in 277 female and 606 male patients in the open-label, multinational trial over 96 weeks. The trial is registered with ClinicalTrials.gov, number NCT00272779.
Methods
Treatment-naive patients aged ≥18 years with HIV-1 RNA ≥5000 copies/mL were randomized to receive either atazanavir/ritonavir 300/100 mg once daily or lopinavir/ritonavir 400/100 mg twice daily, with fixed-dose tenofovir/emtricitabine 300/200 mg once daily.
Results
At week 96, confirmed virological response rates (HIV RNA <50 copies/mL; intent-to-treat analysis) were higher in women and men receiving atazanavir/ritonavir than those receiving lopinavir/ritonavir and lower in women than men in both treatment arms (67% of women and 77% of men on atazanavir/ritonavir and 63% of women and 71% of men on lopinavir/ritonavir). These differences were not observed in the on-treatment analysis. Mean change in CD4 cell count from baseline to week 96 was 265 cells/mm3 for women and 269 cells/mm3 for men on atazanavir/ritonavir and 298 cells/mm3 for women and 286 cells/mm3 for men on lopinavir/ritonavir. Discontinuation rates were higher in women than men in each treatment arm (22% of women and 15% of men on atazanavir/ritonavir and 29% of women and 18% of men on lopinavir/ritonavir). In women and men, grade 2–4 nausea and diarrhoea were more frequent in the lopinavir/ritonavir group; jaundice and hyperbilirubinaemia occurred more frequently in the atazanavir/ritonavir group.
Conclusions
Once-daily atazanavir/ritonavir is an effective and well-tolerated therapeutic option for women and men with HIV-1 infection. The sex-based differences in response may be due to higher discontinuation rates in women.
doi:10.1093/jac/dkq457
PMCID: PMC3019087  PMID: 21148235
antiretroviral therapy; protease inhibitors; HIV
24.  Duffy-Null–Associated Low Neutrophil Counts Influence HIV-1 Susceptibility in High-Risk South African Black Women 
The Duffy-null trait and ethnic neutropenia are highly prevalent in Africa. The authors found that the trait of Duffy-null–associated low neutrophil counts associated with increased HIV-1 susceptibility. The possible contribution of this trait to the high prevalence of HIV-1 in Africa requires further investigation
Background. The Duffy-null trait and ethnic netropenia are both highly prevalent in Africa. The influence of pre-seroconversion levels of peripheral blood cell counts (PBCs) on the risk of acquiring human immunodeficiency virus (HIV)–1 infection among Africans is unknown.
Methods. The triangular relationship among pre-seroconversion PBC counts, host genotypes, and risk of HIV acquisition was determined in a prospective cohort of black South African high-risk female sex workers. Twenty-seven women had seroconversion during follow-up, and 115 remained HIV negative for 2 years, despite engaging in high-risk activity.
Results. Pre-seroconversion neutrophil counts in women who subsequently had seroconversion were significantly lower, whereas platelet counts were higher, compared with those who remained HIV negative. Comprising 27% of the cohort, subjects with pre-seroconversion neutrophil counts of <2500 cells/mm3 had a ∼3-fold greater risk of acquiring HIV infection. In a genome-wide association analyses, an African-specific polymorphism (rs2814778) in the promoter of Duffy Antigen Receptor for Chemokines (DARC −46T > C) was significantly associated with neutrophil counts (P = 7.9 × 10−11). DARC −46C/C results in loss of DARC expression on erthyrocytes (Duffy-null) and resistance to Plasmodium vivax malaria, and in our cohort, only subjects with this genotype had pre-seroconversion neutrophil counts of <2500 cells/mm3. The risk of acquiring HIV infection was ∼3-fold greater in those with the trait of Duffy-null–associated low neutrophil counts, compared with all other study participants.
Conclusions. Pre-seroconversion neutrophil and platelet counts influence risk of HIV infection. The trait of Duffy-null–associated low neutrophil counts influences HIV susceptibility. Because of the high prevalence of this trait among persons of African ancestry, it may contribute to the dynamics of the HIV epidemic in Africa.
doi:10.1093/cid/cir119
PMCID: PMC3115278  PMID: 21507922
25.  Adherence to Antiretroviral Prophylaxis for HIV Prevention: A Substudy Cohort within a Clinical Trial of Serodiscordant Couples in East Africa 
PLoS Medicine  2013;10(9):e1001511.
Jessica Haberer and colleagues investigate the association between high adherence to antiretroviral pre-exposure prophylaxis and HIV transmission in a substudy of serodiscordant couples participating in a clinical trial.
Please see later in the article for the Editors' Summary
Background
Randomized clinical trials of oral antiretroviral pre-exposure prophylaxis (PrEP) for HIV prevention have widely divergent efficacy estimates, ranging from 0% to 75%. These discrepancies are likely due to differences in adherence. To our knowledge, no studies to date have examined the impact of improving adherence through monitoring and/or intervention, which may increase PrEP efficacy, or reported on objective behavioral measures of adherence, which can inform PrEP effectiveness and implementation.
Methods and Findings
Within the Partners PrEP Study (a randomized placebo-controlled trial of oral tenofovir and emtricitabine/tenofovir among HIV-uninfected members of serodiscordant couples in Kenya and Uganda), we collected objective measures of PrEP adherence using unannounced home-based pill counts and electronic pill bottle monitoring. Participants received individual and couples-based adherence counseling at PrEP initiation and throughout the study; counseling was intensified if unannounced pill count adherence fell to <80%. Participants were followed monthly to provide study medication, adherence counseling, and HIV testing. A total of 1,147 HIV-uninfected participants were enrolled: 53% were male, median age was 34 years, and median partnership duration was 8.5 years. Fourteen HIV infections occurred among adherence study participants—all of whom were assigned to placebo (PrEP efficacy = 100%, 95% confidence interval 83.7%–100%, p<0.001). Median adherence was 99.1% (interquartile range [IQR] 96.9%–100%) by unannounced pill counts and 97.2% (90.6%–100%) by electronic monitoring over 807 person-years. Report of no sex or sex with another person besides the study partner, younger age, and heavy alcohol use were associated with <80% adherence; the first 6 months of PrEP use and polygamous marriage were associated with >80% adherence. Study limitations include potential shortcomings of the adherence measures and use of a convenience sample within the substudy cohort.
Conclusions
The high PrEP adherence achieved in the setting of active adherence monitoring and counseling support was associated with a high degree of protection from HIV acquisition by the HIV-uninfected partner in heterosexual serodiscordant couples. Low PrEP adherence was associated with sexual behavior, alcohol use, younger age, and length of PrEP use.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, about 2.5 million people (mostly living in sub-Saharan Africa) become infected with HIV, the virus that causes AIDS. HIV, which is usually transmitted through unprotected sex with an HIV-infected partner, destroys immune system cells, leaving infected individuals susceptible to other infections. There is no cure for AIDS, although antiretroviral drugs can hold HIV in check, and there is no vaccine against HIV infection. Individuals can reduce their risk of HIV infection by abstaining from sex, by having only one or a few low risk sexual partners, and by always using a condom. In addition, antiretroviral drugs can potentially be used in two ways to reduce HIV transmission. First, these drugs could be given to HIV-positive individuals to reduce their infectiousness. Second, antiretroviral drugs could be given to HIV-uninfected people to reduce acquisition of the virus. This approach—pre-exposure prophylaxis (PrEP)—has provided varying levels of protection against HIV infection in randomized controlled trials (RCT; studies that monitor the outcomes of groups of patients randomly assigned to receive different test drugs or a placebo/dummy drug).
Why Was This Study Done?
One hypothesis for the varying efficacy of PrEP in RCTs is differential adherence—differences in whether trial participants took the antiretroviral drugs correctly. Antiretroviral drugs only control HIV infections effectively when they are taken regularly and adherence to antiretroviral PrEP is probably also important for HIV prevention. Here, the researchers investigate adherence to antiretroviral prophylaxis in a substudy within the Partners PrEP Study, a placebo-controlled RCT of oral antiretroviral drugs among nearly 5,000 HIV-uninfected members of serodiscordant couples in East Africa. In serodiscordant couples, only one partner is HIV-positive; 20% of couples in Africa who know their HIV status are serodiscordant. In the Partner PrEP Study, the efficacy of HIV protection with oral antiretroviral drugs was 67%–75%.
What Did the Researchers Do and Find?
The researchers selected a “convenience” sample—a sample is taken non-randomly from a population that is close at hand—of 1,147 HIV-uninfected partners enrolled in Uganda. They used unannounced home-based pill counts (an approach that reduced the chance of participants dumping unused pills to appear more adherent than they actually were) and electronic pill bottle monitoring (a microchip in the medication bottle cap recorded whenever the bottle was opened) to measure PrEP adherence in this cohort. All the participants received adherence counseling at PrEP initiation and throughout the study; counseling was intensified if unannounced pill count adherence fell below 80%. Fourteen participants, all of whom had been assigned to placebo, became HIV-positive during the adherence substudy. The average adherence to PrEP was 99.1% and 97.2% as measured by unannounced pill counts and by electronic monitoring, respectively. About 7% and 26% of participants had less than 80% adherence as measured by unannounced pill count and electronic monitoring, respectively, during at least one 3-month period of the substudy. Greater than 80% adherence was associated with the first 6 months of PrEP use and polygamous marriage. Adherence less than 80% was associated with report of no sex or sex with another person besides the study partner, younger age, and heavy alcohol use. Finally, the adherence intervention (intensified counseling) was well received and in the first unannounced pill count after the intervention, adherence increased to above 80% in 92% of participants.
What Do These Findings Mean?
These findings indicate that the high level of PrEP adherence achieved in the setting of active adherence monitoring and counseling support was associated with a high level of protection from HIV acquisition by the HIV-uninfected partner in heterosexual serodiscordant couples. The findings also suggest that low PrEP adherence is associated with sexual behavior, alcohol use, younger age, and length of PrEP use. Several aspects of the study design may limit the accuracy of these findings. For example, although the adherence measures used here are probably more accurate than participant reports of missed doses and clinic-based pill counts (adherence measures that are often used in RCTs), they are not perfect. Nevertheless, these findings provide further support for the ability of PrEP to prevent HIV acquisition when taken regularly; they suggest that adherence interventions in the implementation setting should address sexual behavior, risk perception, and heavy alcohol use; and they provide data to guide ethical decisions about resource allocation for prevention and treatment of HIV infection.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001511.
The 2012 UNAIDS World AIDS Day Report provides up-to-date information about the AIDS epidemic and efforts to halt it
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, summaries of recent research findings on HIV care and treatment, and information on HIV transmission and prevention and on PrEP
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV and AIDS in Uganda, on HIV prevention, and on PrEP (in English and Spanish)
PrEP Watch provides detailed information about PrEP and links to other resources; it includes personal stories from people who have chosen to use PrEP
More information about the Partners PrEP Study is available
Personal stories about living with HIV/AIDS are available through Avert, through Nam/aidsmap, and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001511
PMCID: PMC3769210  PMID: 24058300

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