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50% of New HIV Infections Occur When Transmitter is Newly Infected
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Newly infected spread half of HIV
McGill study finds high-risk people often don't know they have virus
LISA PRIEST
Globe and Mail
Half of all new HIV transmissions occur when people are unlikely to know they carry the virus and in some cases, wouldn't test positive for it because they are so newly infected, a Canadian study says.
The study, to be published in the April edition of the Journal of Infectious Diseases, is one of the first in the world to quantify how many of the newly infected are responsible for spreading the disease to others.
And it raises troubling questions about how to deal with the problem: How can those at high risk be encouraged to come forward and undergo frequent, repeated tests when no one knows who they are? And should those at very high risk of contracting the disease be put on anti-retroviral therapy as a preventive measure?
"From the standpoint of public health, we have a major problem in Canada and North America," study author Mark Wainberg, director of the McGill University AIDS Centre at the Jewish General Hospital, said in a telephone interview yesterday.
"... One of the things driving this entire epidemic is that people themselves are newly infected and are often the most infectious they will ever be throughout their lives and often not even know it."
Those who have just become infected with HIV are at their most infectious as the virus madly replicates, making millions of copies. The immune system responds by launching a battle on the virus and making antibodies.
Those going through this process, medically referred to as seroconversion, report flu-like symptoms, including fever and chills. Others, however, feel no differently.
Most people, after being exposed to the virus, would test positive for it two to four weeks later; others may not test positive for the virus that causes AIDS until three and as long as six months later, said Rita Shahin, associate medical officer of health with Toronto Public Health.
"This is an important study," said Dr. Shahin, who was not involved in the research. "We've always known that people who don't know their HIV status are accounting for a significant percentage of transmissions. This further narrows it down to that group who are within the first six months of infection."
She recommended testing of high-risk individuals every three to six months. Other efforts have included putting condoms in bathhouses, counselling and education.
Dr. Wainberg said those who learn of being HIV positive often modify their behaviour so as not to put others at risk.
But modifying behaviour is not necessarily an option when someone does not even know or suspect they have the disease.
At the end of 2005, an estimated 58,000 people in Canada were living with HIV infection, including AIDS. This represents an increase of about 16 per cent from the 2002 estimate of 50,000. Of those, 27 per cent would be unaware of their infection, according to Public Health Agency of Canada figures.
An accompanying editorial to the journal article, also posted online, stated it is time to evaluate the most potent intervention to treat the disease -- highly active anti-retroviral therapy -- as a form of prevention.
"HAART is no replacement for enhanced behavioural approaches to reduce transmission," the editorial says. "It is expensive, and relatively toxic, and many regions of the world still have not implemented therapy to many of their infected populations. However, we argue that the current focus on increasing HIV diagnoses through more widespread testing requires a parallel strategy for minimizing ongoing transmission."
However, the editorial goes on to say "it is now time to evaluate application of the most potent intervention to treat this disease -- namely, an anti-retroviral therapy -- to its prevention."
Dr. Wainberg agreed with the sentiment, saying that there are clinical trials under way to determine whether the drugs to treat the disease can be used to prevent transmission among very high-risk groups, such as sex workers in the developing world.
"We know through a study that came out a month ago that microbicides are not yet ready for prime time," he said in a telephone interview from Los Angeles, where he was attending a conference. "A related concept is giving them drugs orally as preventives."
He also recommended that public-health officials try to identify high-risk people and encourage them to be tested, as well as providing more rapid testing.
Half of HIV transmitters unaware, survey says
CanWest News Service; Montreal Gazette
Published: Saturday, March 17, 2007
MONTREAL - Half of new HIV transmissions happen when newly infected people don't know they are carrying the virus and don't even test positive for it, a new study shows.
The study, presented Friday at an AIDS symposium in Montreal, provoked questions on how to deal with the problem of treating unknown sources of infection - including mass screening and using antiretroviral therapy for prevention.
"People are most likely to transmit the AIDS virus when they are first infected than in the chronic stages of the illness," co-researcher Michel Roger of the Universite de Montreal said.
A team led by Dr. Mark Wainberg, director of the McGill AIDS Centre, followed 2,500 HIV patients in several Montreal clinics over eight years.
An estimated 30 per cent of people with HIV don't know they are infected, which makes it important but difficult to identify them, Wainberg said.
The study, to be published in the April edition of the Journal of Infectious Disease, is among the first to quantify how newly infected people spread the virus to others.
Roger described HIV-positive people who are unaware of their status as "walking transmission bombs."
Almost 40 million people worldwide - nearly 60,000 in Canada - are infected with HIV, or human immunodeficiency virus, which causes AIDS. The virus multiplies quickly, starting immediately after infection.
The following are excerpts from the original article by Wainberg et al and an accompanying Editorial in JID
High Rates of Forward Transmission Events after Acute/Early HIV-1 Infection
The Journal of Infectious Diseases April 1, 2007;195:951-959
Mark A. Wainberg,1 and the Quebec Primary HIV Infection Study Groupa
1McGill AIDS Centre-Jewish General Hospital,
Early infection accounts for approximately half of onward transmissions in this urban North American study. Therapy at early stages of disease may prevent onward HIV transmission.
Taken together, our findings indicate that PHI can account for a high proportion of HIV transmissions. Acute/early infection is characterized by high viremia and high viral set points in the absence of treatment [1]. Acute/early infections are often undiagnosed, leading to high risk behavior, and unprotected sex may facilitate transmission. Relatively homogeneous viral quasispecies exist at early stages of infection, enhancing the selective advantage of clonal transmissible species [16, 30]. Many multiresistant variants that arise in treated individuals show reduced viral replicative fitness and transmissibility [30]. HIV-1-specific immunity may not arise during the first 2-4 months after PHI, and early immune responses may decrease rapidly in the absence of treatment [34]. Treatment of CI patients reduces circulating viremia, a critical factor in HIV transmission.
It is important to actively seek out recently infected persons and to propose counselling to reduce high risk behavior during this critical period [1, 3, 35-37]. Our findings further underscore recommendations for genotyping in primary/early infection to document clustering of infection and to provide information on transmitted drug resistance, both as an issue in public health and as a guide to future therapy [37].
The potential benefits of highly active antiretroviral therapy (HAART) in early infection may therefore be 2-fold. HAART may lower the risk of onward transmission, and, in addition, patients may potentially benefit from better immune control and lower set points of viremia [1, 26, 27]. Initiation of HAART during acute infection may be associated with durable virologic and immunologic benefits for >72 weeks, compared with no treatment [26]. Although some people who have newly diagnosed HIV infection may have already transmitted the virus to others by the time of initiation of HAART, early treatment intervention may nonetheless prevent significant numbers of additional transmissions.
EDITORIAL
Primary HIV Infection, Phylogenetics, and Antiretroviral Prevention
Deenan Pillay1 and Martin Fisher2
1Centre for Infections, Health Protection Agency, and Department of Infection, University College London, and 2Department of HIV/Genitourinary Medicine, Brighton and Sussex University Hospitals, Brighton, United Kingdom
Over the past 10 years, the world has witnessed one of the most significant chronic disease interventions ever seen-that of highly active antiretroviral therapy (HAART) for HIV infection. Morbidity and mortality have plummeted in those areas of the world with unrestricted access to these drugs [1], and HIV/AIDS has been transformed from an almost certain death sentence to, for those receiving treatment, a long-term, manageable disease, with a potentially normal life expectancy. By contrast, this success has not been matched by reductions in HIV transmissions over the same period. Indeed, current surveillance data suggest that transmissions are increasing in resource-rich communities-particularly among men who have sex with men (MSM) [2], in addition to the large epidemics ongoing within the resource-poor world. Such increases represent a public health failure. The inevitable outcome of widespread HAART use in the midst of increasing HIV transmission-namely, transmission of drug-resistant viruses-has now become a worldwide reality [3-5].
In this issue of the Journal, Brenner et al. [13] have used phylogenetic analyses on such a local sequence data set to explore the likely source of new infections in the mainly MSM Quebec cohort. They use well-established methods of HIV-1 pol gene analysis, incorporating very high bootstrap values and low genetic distance criteria, to demonstrate the high transmission rate from those with primary HIV infection (PHI) and show that nearly 50% of acute infections within their cohort as a whole are linked to other primary infections. As discussed above, phylogenetic analyses on their own cannot provide definitive evidence for transmission events; however, the consistency between this and other studies using such phylogenetic techniques in individuals with PHI [14, 15] suggests that their conclusion-that primary infection is a critical period for onward transmission of HIV-is valid.
This assertion is biologically plausible because PHI represents a period of extremely high viral load levels. Indeed, prospective longitudinal studies among heterosexual HIV-1 serodiscordant couples in the developing world have clearly demonstrated that viral load and early stage of infection are predictors of transmission [16, 17], alongside the presence of sexually transmitted infections [18] and circumcision status [19]. Large prospective studies continue to investigate the impact of empirically or syndromically treating sexually transmitted infections or suppressing herpes simplex infection, as well as the use of male circumcision, on reductions in transmission.
However, these strategies may be of limited effectiveness if individuals at or near to PHI represent a major source of onward transmission, because many such interventions depend on an initial positive diagnosis. It is well recognized that the symptoms associated with PHI are nonspecific, and this entity frequently remains undiagnosed by health care providers. Indeed, it is estimated that only a small proportion of infected individuals are diagnosed in early infection [20]. By contrast, active ascertainment and high levels of testing can improve the diagnosis of recent infection, to the extent that up to 50% of recent infections can be identified [21]. Normalization of HIV testing within health care settings, such as the policy recently announced by the Centers for Disease Control and Prevention, is clearly a major advance [22]. However, it must be recognized that selection of testing strategies must also be appropriate for optimizing the detection of early infection, such as combined antibody-antigen tests [23] or pooled HIV-RNA testing [24].
What are the advantages of early HIV diagnosis with regard to prevention of transmission? First, it is recognized that an HIV diagnosis per se results in subsequent risk reduction [25]. However, more contentious is the potential role of antiretroviral therapy in reducing transmission. Although reductions in plasma viremia are mirrored by reductions in the transmissible virus in the genital tract [26], there has been little discussion of the prevention role of HAART outside of mother-to-child transmission and, more recently, preexposure prophylaxis scenarios [27]. Current guidelines for initiating HAART are based on the risk-benefit for the infected individual, and treatment is rarely recommended with a CD4 cell count >350 cells /L [11]. As clinical management of HIV infection improves and HAART suppression of viremia is maintained for longer periods of time, the source of further transmissions will shift more toward untreated (including undiagnosed) individuals. We should therefore consider the role of extending treatment to those with higher CD4 cell counts, for benefit of individual and community. Such an extension can now be contemplated in light of recent improvements in drug formulations (thus enhancing adherence) and reductions in HAART toxicities [28]. Indeed, one study of HAART use at high CD4 cell counts to prevent transmission in discordant couples is underway [29]. A possible implication of such a policy could be the risk of emergence of drug resistance and subsequent transmission. Against this must be cited the low risk of resistance emerging for those starting on current HAART triple therapies [30]. Indeed, as treatment efficacy continues to improve, an increasing proportion of transmitted resistance is likely to originate from untreated individuals [31], who are themselves infected with resistant strains and in whom high levels of viremia persist without reversion of virus to wild type [32]. This, therefore, identifies a further reason for extending treatment.
Changing the paradigm of treatment rationale is even more pertinent for primary infection. Trials of short-term HAART in the setting of PHI are currently under way [33]. Such trials are largely constructed around the potential immunological and virological benefits for the treated individual. In view of the recognition of primary infection as a major driver of transmission, we argue that the reduction of transmission risk, by reducing viral load, should also be considered as a measurable benefit of early interventions.
HAART is no replacement for enhanced behavioral approaches to reduce transmission. It is expensive, and relatively toxic, and many regions of the world still have not implemented therapy to many of their infected populations. However, we argue that the current focus on increasing HIV diagnoses through more widespread testing requires a parallel strategy for minimizing ongoing transmission. Through cohort and molecular epidemiological studies, the importance of early infection in maintaining these transmissions will be better understood. It is now time to evaluate application of the most potent intervention to treat this disease-namely, antiretroviral therapy-to its prevention. Furthermore, strategies to improve recognition of recent infection, in addition to identifying undiagnosed chronic infection, are crucial for effective implementation of prevention strategies.
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