When to Start ART: Two Major Cohort Studies Published

Paul E. Sax, MD

One study suggests that treatment should be started before the CD4 count falls below 350 cells/mm3; the other suggests before 500 cells/mm3.

Because no prospective clinical trial has directly addressed the issue of immediate versus deferred antiretroviral therapy (ART) for asymptomatic HIV-infected patients, clinical guideline panels have relied mainly on cohort study data to inform their recommendations. This month, findings were published from two major collaborative cohort studies, both of which were presented at scientific meetings in the past year (JW AIDS Clin Care Nov 10 2008 and Mar 9 2009).

In the NA-ACCORD study, investigators conducted two parallel analyses using data pooled from 22 cohorts in North America. Patients were eligible for the first analysis if, at any point during the study period (19962005), they had a CD4 count of 351 to 500 cells/mm3 and no history of AIDS-defining illness or ART use. Of the 8362 patients who met these criteria, 2084 started ART immediately (within 6 months after entering the CD4-cell range of interest), and 6278 deferred. Deferral of therapy was associated with a 69% increased risk for death during follow-up. The second analysis was identical to the first, except that patients had CD4 counts >500 cells/mm3. Again, only about 25% of patients (2220 of 9155) started ART immediately, and deferral of therapy was associated with a significant increase in mortality risk (94%). In both analyses, patients who started ART earlier generally had more-favorable baselinecharacteristics (e.g., lower rates of injection-drug use [IDU] and hepatitis C virus coinfection), and they achieved higher rates of virologic suppression with treatment, suggesting a better rate of medication adherence. However, even after adjustment for some of these factors, the survival advantage of earlier therapy remained.

The merits of early therapy were also assessed by the When to Start Consortium, which evaluated pooled data from 15 cohorts in Europe and North America. Patients were eligible for analysis if they started ART in 1998 or later with a CD4 count <550 cells/mm3, no history of AIDS-defining illness, and a presumed acquisition mode other than IDU. In order to estimate the lead time before starting therapy and the clinical events that took place during this time, the investigators applied cohort data from the pre-ART era (19891995) to the current era. More than 24,000 patients were included in the analysis. Deferral of ART until the CD4 count fell to between 251 and 350 cells/mm3 (compared with 351450 cells/mm3) was associated with a 28% increased risk for AIDS or death; no significant increase was seen for death alone. Comment
These two studies represent a fascinating example of how advanced statistical techniques can be applied to observational data to try and answer a clinical question in this case, when to start ART in asymptomatic patients. Although the observational nature of these studies prevents either research group from claiming to "prove" that therapy should be started at higher CD4-cell counts a point that both editorials hasten to mention the data do add to a substantial body of evidence showing that untreated HIV infection has negative consequences, even at higher CD4- cell counts. (Neither study can claim that those who start ART earlier are the same as those who defer they may have been more "health seeking" and hence did better for reasons unrelated to ART.) The NA-ACCORD data are particularly striking and are even stronger than those presented at the 2009 Retrovirus Conference. Although the two research groups reach different conclusions about the precise threshold for when to start therapy, they are consistent in the most important message that treatment should be started before the CD4 count falls below 350 cells/mm3, and perhaps earlier.

Paul E. Sax, MD

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Rapid HIV Testing in Emergency Departments - Beware of False Positives

Carlos del Rio, MD

In a low-prevalence ED, rapid tests often ruled out HIV, but, when reactive, they often yielded false-positive results.

In 2006, the CDC recommended routine HIV testing for all adults and adolescents in all healthcare settings, including emergency departments (EDs; AIDS Clin Care Oct 6 2006). This recommendation, coupled with the availability of rapid HIV tests, has resulted in a variety of efforts to increase HIV screening in EDs. However, many concerns remain (JAMA 2008; 300:945), such as the feasibility of testing in this setting, mainly because of the resources required (AIDS Clin Care Jan 14 2008), and the specificity of rapid oral-fluid tests (AIDS Clin Care Jul 7 2008).

In the present study, investigators evaluated the performance of the OraQuick Advance Rapid HIV-1/2 Antibody Test in the context of a clinical trial conducted in a busy ED in Boston. All rapid tests were performed using oral fluid, and all reactive tests were followed by a Western blot, an EIA, and measurement of both CD4-cell count and plasma viral load. During an 8-month period in 2007, 2356 ED patients were invited to participate in the HIV testing trial; 1397 (59.3%) agreed.

Of the 854 who actually underwent rapid testing, 849 had interpretable results. Thirty-nine patients (4.6%) had reactive tests. Of the 31 who agreed to confirmatory testing, only 5 were found to be HIV-infected, for an overall HIV prevalence of 0.6%; the others were catalogued as not infected. In this setting, the estimated specificity of the test was 96.9% (95% confidence interval, 95.7%-98.1%), which was significantly lower than the specificity reported by the manufacturer (99.8%; 95% CI, 99.6%-99.9%).

Comment
This HIV testing program was considered a success, because many patients who otherwise would not have been tested left the ED knowing that they were not HIV-infected. However, we clearly need better ways to confirm or rule out the presence of HIV infection in patients whose rapid tests are reactive. The authors suggest including viral-load testing in the panel of confirmatory tests, along with Western blot and EIA.
Carlos del Rio, MD

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Circumcision Status and HIV Infection Among MSM in the U.S.

Rebeca M. Plank, MD

Summary
Circumcision can reduce the risk for heterosexually acquired HIV infection (ACC Mar 19 2007), but does it have similar benefits in men who have sex with men (MSM)? To explore this possibility, researchers conducted a cross-sectional study among 1079 black MSM and 957 Latino MSM in three U.S. cities. Participants underwent HIV testing and provided information about demographic factors, high-risk behaviors, and circumcision status.

Seventy-four percent of black MSM reported being circumcised, compared with 33% of Latino MSM (P<0.0001). In both groups, circumcised men were more likely than uncircumcised men to be U.S.-born or to have U.S.-born parents. Among blacks, circumcised men were more likely to self-identify as gay (vs. bisexual or heterosexual), to be older, to have higher levels of education and income, and to report recent use of marijuana or amyl nitrates; they were also more likely to report being the receptive partner in anal sex and to have recently engaged in unprotected anal intercourse. Among Latinos, circumcised men were more likely than uncircumcised men to report recent use of cocaine and heroin; they also reported more-frequent and more-recent HIV testing. In multivariate analyses, circumcision status was not associated with HIV serostatus in either ethnic group. Similar null results were found when analyses were limited to men who have sex only with men and when analyses were even further limited to men who acted exclusively as the insertive partner during recent unprotected anal intercourse. Comment
Although circumcision cannot be expected to protect an individual from HIV infection during receptive anal intercourse, results from this cross-sectional study suggest that it does not protect individuals during insertive anal intercourse either. Two previous observational studies among MSM showed a doubling of HIV risk among uncircumcised men (J Infect Dis 1993; 168:1404 and J Acquir Immune Defic Syndr 2005; 39:82), but those studies included very few black or Latino men. These groups are affected disproportionately by the HIV epidemic in the U.S. and are also less likely than whites to be circumcised. Furthermore, in one of these studies, several other factors played a larger role in HIV seroconversion than did circumcision status. Overall, results from these observational studies have not made a compelling case for circumcision as an HIV-prevention tool among MSM in the U.S.
Rebeca M. Plank, MD

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Vaccination of HIV-infected Adults

LBS Gelinck; FP Kroon

Abstract
Vaccination has been shown to be one of the most powerful tools to decrease morbidity and mortality caused by an array of infectious diseases. The risk and complications of some vaccine-preventable diseases is higher in HIV-infected individuals, underscoring the importance of vaccination in these patients. However, the immune response upon vaccination is generally impaired and shorter lasting in HIV-infected individuals, especially in those with low CD4+ T-lymphocyte counts and detectable HIV RNA, as compared with healthy controls.

Even in patients responding to antiretroviral treatment, an impaired immune response may persist despite normalization of the CD4+-cell count. Caution with live-attenuated vaccines is warranted in HIV-infected individuals with low CD4 T-lymphocyte counts. Decisions regarding administering a live-attenuated vaccine should be made after weighing the risks and benefits on an individual basis. In this article the immunology of vaccination in HIV-infected individuals, as well as the most relevant caveats of vaccination in this patient group, are reviewed in addition to the currently available information concerning the influenza A/H1N1 2009 monovalent vaccine.

Introduction
Preventing or mitigating disease by vaccination is one of the most (cost-)effective interventions in medicine. Routine vaccination programs for adults, which typically include booster vaccinations every decade against diphtheria, tetanus, pertusis and polio, also apply to HIV-infected adults. In addition, influenza, pneumococcal, hepatitis A virus and HBV vaccines are indicated in (most) HIV-infected adults. However, the effectiveness andsafety of vaccines that prevent travel-associated infections might be lower in HIV-infected individuals as compared with healthy individuals.

Numerous clinical and immunological factors have been correlated with an impaired immune response upon vaccination; most notably a low CD4 T-cell count and detectable HIV RNA at the time of vaccination. Most clinical and immunological vaccination studies in HIV-infected individuals, including our own studies, are relatively small in sample size and rely on surrogate parameters, such as antibody titers, as the primary outcome. This article summarizes the general principles of vaccination of HIV-infected adults, with the currently registered vaccines (thus excluding HIV vaccines and other vaccines in development) and refers to relevant practical guidelines.

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Male Circumcision and Neisseria Gonorrhoeae, Chlamydia Trachomatis and Trichomonas Vaginalis : Observations After a Randomised Controlled Trial for HIV Prevention

J. Sobngwi-Tambekou; D. Taljaard; M. Nieuwoudt; P. Lissouba; A. Puren; B. Auvert

Abstract
Objective: To assess the association between male circumcision and Neisseria gonorrhoeae, Chlamydia trachomatis and Trichomonas vaginalis using data from a male circumcision randomised controlled trial.

Methods: We used data collected during the male circumcision trial conducted in Orange Farm (South Africa) among men aged 18-24 years. Altogether, 1767 urine samples collected during the final follow-up visit were analysed using PCR. Prevalence of N gonorrhoeae, C trachomatis and T vaginalis was assessed as a function of male circumcision using odds ratios (OR) given by univariate and multivariate logistic regression.

Results: In an intention-to-treat analysis, prevalence of N gonorrhoeae, C trachomatis and T vaginalis among intervention and controlgroups were 10.0% versus 10.3% and 1.7% versus 3.1%, respectively. The association between T vaginalis and male circumcision remained borderline when controlling for age, ethnic group, number of lifetime partners, marital status, condom use and HIV status. In the as-treated analysis, this association became significant.

Conclusions: This study demonstrates for the first time that male circumcision reduces T vaginalis infection among men.This finding explains why women with circumcised partners are less at risk for T vaginalis infection than other women. The protective effect on T vaginalis is an additional argument to recommend male circumcision in Africa where it is acceptable.

Introduction
Recent evidence has shown that male circumcision is a promising prevention approach for sexually transmitted infections (STIs): three randomised controlled trials (RCTs) have shown that male circumcision reduces HIV infection among young men in Africa. According to a meta-analysis published in 2006, circumcised men may be at lower risk of herpes simplex virus 2 (HSV-2) infection, chancroid and syphilis. However, there are conflicting results about the association of male circumcision and non-ulcerative STIs such as Neisseria gonorrhoeae, Chlamydia trachomatis and Trichomonas vaginalis infections among men.

Infection with non-ulcerative STIs is major public health issue. There are about 62 million new cases of N gonorrhoeae annually worldwide, with an estimated incidence of 17 million in sub-Saharan Africa. N gonorrhoeae is asymptomatic in only 10% of men but primarily asymptomatic in women and its complications can be lethal. C trachomatis worldwide incidence has been estimated at 92 million annually, with about 16 million occurring in sub-Saharan Africa. It is a significant public health concern because C trachomatis infection is asymptomatic in over 50% of cases among men and women and it can lead to serious health complications if untreated.

Finally, T vaginalis is the most common non-viral STI in the world, with 174 million new cases estimated in 1999. In sub-Saharan Africa, the incidence is estimated at 32 million. The infection is asymptomatic in about 50% of infected women and in over 90% of men; thus, re-infection and re-exposure is problematic. Furthermore, co-infections among these three STIs are common.

The objective of this study was to analyse the effect of male circumcision on N gonorrhoeae, C trachomatis and T vaginalis prevalence using data collected during a male circumcision RCT conducted in Orange Farm, South Africa.

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Increases in Gonorrhea Among High School Students Following Hurricane Katrina

M. J. Nsuami; S. N. Taylor; B. S. Smith; D. H. Martin

Abstract
Objective: To determine the prevalence of Neisseria gonorrhoeae in a student population before hurricane Katrina and after their residential neighbourhoods were devastated in the wake of the hurricane.

Methods: Students in a New Orleans public high school were offered urine screening for N gonorrhoeae and Chlamydia trachomatis using nucleic acid amplification tests before (n = 346) and after (n = 333) hurricane Katrina. Based on studies showing gonorrhea clustering in physically deteriorated neighbourhoods, it was hypothesised that the post-Katrina gonorrhea prevalence would be higher among students whose neighbourhoods still showed signs of deterioration in the aftermath of the hurricane.

Results: Before and after hurricane Katrina, the prevalence of gonorrhea increased from 2.3%, respectivel. In logistic regression of gonorrhea controlling for gender, age, chlamydia infection and exposure to hurricane-affected residential neighbourhood conditions, gonorrhea was significantly associated with female gender and with chlamydia infection. Although of weak statistical significance, there was a strong independent positive trend toward testing positive for gonorrhea after the hurricane.

Conclusions: The analysis indicates that the odds of testing positive for gonorrhea more than doubled among students after the hurricane, indicating that surveillance activities should be restored to monitor sexually transmitted infections (STIs) among at-risk populations. Redoubled efforts should be put into STI screening programmes as soon as possible following natural disasters to prevent resurgent STI incidence rates.

Introduction
If things haven't changed by our next visit, we may have to announce a revolution.Mikhail Gorbachev, Former Soviet President, while touring the Lower-Ninth Ward in New Orleans on 5 October 2007 Populations affected by a natural disaster face health threats that include the spread of communicable diseases. The risks of communicable diseases following a natural disaster are particularly higher among displaced populations and are proportional to population density. Watson and colleagues from the Humanitarian Emergencies Program at the World Health Organization recently reviewed communicable disease outbreaks that have affected populations displaced by natural disasters around the world. Displaced populations following earthquakes, floods, tsunamis, volcanoes, typhoons or hurricanes have suffered outbreaks of diarrhoeal diseases, acute respiratory infections, measles, meningitis and malaria among others. It is estimated that between 60% and 95% of reported deaths among refugees and displaced populations are attributed to malnutrition, diarrhoeal diseases, measles, acute respiratory infections and malaria.

In addition to these health threats to displaced populations, the physical damage to residential neighbourhoods and to public health and clinical care infrastructures force individuals temporarily displaced who return in their disaster affected areas and those who do not evacuate to live for months or years, depending on the pace of recovery, in neighbourhoods characterised by a certain degree of deterioration with inadequate access to primary healthcare services. Studies have reported associations between physically deteriorated neighbourhoods and poor health. These associations suggest that the neighbourhood physical deterioration in the wake of a natural disaster can increase the vulnerability of affected populations to poor health.

Applying the boarded-up housing characteristics of the US Census Bureau and the broken windows theory in sexually transmitted disease (STD) research, Cohen et al found a clustering of gonorrhea cases in physically deteriorated neighbourhoods in 107 US cities, independent of individual factors that included race, poverty, unemployment, marital status, level of education and lack of insurance. Although, in disaster emergency response, communicable diseases of primary concerns are diseases associated with high transmissibility, high morbidity and high mortality such as waterborne, airborne or vectorborne diseases, in the long term, the ecological studies by Cohen et al provide grounds for considering an association between deteriorated neighbourhood conditions in the wake of a natural disaster and STDs. Despite expressed concerns for sexually transmitted infections (STIs) as risk factors for human immunodeficiency virus (HIV) infection in emergency preparedness and response, we were unable to find any published study reporting on the prevalence of STIs before and after a natural disaster.

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Herpes Complex

Cornelis A Rietmeijer; Nicola Low

In a blood-red splatter, the word "Herpes" adorned the cover of Time Magazine of 2 August 1982 along with the tagline : "Today's Scarlet Letter". It appeared to herald an era of heightened public interest for herpes simplex virus (HSV) as a "new" sexually transmitted infection (STI). Of course, this attention was quickly overshadowed by increasing awareness of a really new, but much more serious STI: HIV. In the past 25 years, although perhaps less sensational than the progress in HIV research, studies into HSV, especially the genital variant HSV-2, have yielded many important insights that are now leading to renewed efforts to push the prevention of genital herpes to the foreground, inviting the question as to whether aggressive HSV-2 control efforts are now feasible and, from a public health view, warranted.

First, HSV-2 is much more prevalent than was previously thought. Among the general US population, 17% show serological evidence of infection; up to 40% in the African-American subpopulation. The article by Glynn and colleagues shows that HSV-2 infection was widely spread in parts of sub-Saharan Africa even before the HIV epidemic and that HSV prevalence over time does not seem to have been strongly influenced by the co-occurrence of HIV.

Second, controlling HSV-2 has been seen as a potentially important tool in HIV prevention because of the ample evidence that HSV-2 is an important co-factor in the acquisition of HIV. Third, control of HSV may reduce the incidence of neonatal herpes, a cause of severe morbidity and mortality. Fourth, antiviral HSV-2 therapy is not only effective in treating symptomaticHSV-2 infections, but also reduces HSV genital shedding and reduces HSV transmission to uninfected partners. With more anti-HSV drugs coming off-patent, these drugs are increasingly affordable.

Fifth, type-specific serological tests for HSV are increasingly sensitive and specific and have a high positive predictive value in high prevalence populations. Rapid HSV tests are currently being marketed at prices that will allow them to be considered for routine use in certain clinical settings, for example STI clinics. Finally, clinical trials into preventive HSV-2 vaccines have yielded mixed results thus far and condom use might be only partly effective in preventing HSV transmission. Testing and suppressive treatment for those infected have thus emerged as the mainstay of a possible intervention to prevent the ongoing transmission of HSV.

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Finding sex partners on the internet: what is the risk for sexually transmitted infections?

A A Al-Tayyib; M McFarlane; R Kachur; C A Rietmeijer

Abstract
Objective: To assess the association between sexual encounters with internet partners and current Chlamydia trachomatis (Ct) and Neisseria gonorrhoeae (GC) infections.

Methods: Between August 2006 and March 2008, patients at the Denver Metro Health Clinic were routinely asked about sexual encounters with internet partners. This retrospective case-control study was limited to patients who tested for Ct/GC at their visit. Analyses were stratified by sexual orientation to account for differences in baseline risk behaviours.

Results: Of 14 955 patients with a valid Ct/GC test result, 2802 (19%) were infected with Ct/GC. Stratified by sexual orientation, the prevalence of Ct/GC infection was 17% for men who have sex with men (MSM), 21% for men who have sex with women (MSW) and 16% for women. A total of 339 (23%) MSM, 192 (3%) MSW and 98 (2%) women reported having a sexual encounter with a person they met on the internet in the past 4 months. The estimates of the association between recent internet sex partner and current Ct/GC infection were not significant for MSM (risk ratio (RR): 1.12, 95% confidence interval (CI): 0.84 to 1.49) and women (RR: 0.81, 95% CI 0.45 to 1.48). However, the association appeared to be significantly protective among MSW (RR: 0.66, 95% CI 0.44 to 0.98).

Conclusions: Sexual encounters with internet partners did not appear to be associated with increased risk of current Ct/GC infection among people seeking care at a sexual health clinic. Seeking sexual partners on the internet is a complex behaviour and its implications for STI/HIV infection are not fully understood.

Introduction
With roughly 238 million internet users in the United States and over one billion users worldwide, the internet is a significant part of daily life and has provided a new environment for interaction among internet users. Included in these interactions are opportunities for seeking and meeting sexual partners. The use of the internet as a venue for meeting sexual partners first came to the attention of public health officials after an outbreak of syphilis in San Francisco was traced back to an AOL chat room used predominately by men who have sex with men (MSM).

Since then, several studies have found that those who seek sex partners online are at greater risk for sexually transmitted infections (STI) and HIV infection. However, most studies have used markers for STI/HIV rather than infection status itself, including number of sex partners, unprotected (anal) intercourse or history of STI. Furthermore, in many of these studies, risk behaviours have been compared between people seeking sex online and people who were not. As the latter group more than likely includes individuals at generally lower risk, online sex seeking may have been a marker, rather than the cause, of risky behaviour. Finally, most of the online sex partner research has been conducted among MSM, as this behaviour is more prevalent in this
population.

It is unclear from these studies whether seeking sexual partners on the internet is simply a marker of high-risk sexual behaviours, as we have previously suggested, or whether it actually increases ones risk of acquiring an STI. To our knowledge, no study has evaluated the association between seeking sexual partners online and current STI status. To help elucidate these issues, we analysed data from patients attending an urban STI clinic with the aim of examining the association between self-reports of online sex partnering and current STI, specifically infection with Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (Ct). We postulated that these effects would vary among different sexual orientations and therefore examined each of these groups separately. Finally, to avoid only comparing those who had internet sex-seeking experience with those who never sought sex partners online, we compared those with recent versus those with more distant or non-existent online sex-seeking experiences.

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