WHAT'S NEW THIS THURSDAY: TWO ON DEWORMING OF HIV SEROPOSITIVES, ONE ON THE ORIGINS OF HIV

Monday, 13th of August 2012

• TWO ON DEWORMING OF HIV SEROPOSITIVES; ONE ON THE ORIGINS OF HIV
  
• INTEGRATION OF DEWORMING INTO HIV CARE AND TREATMENT: A NEGLECTED OPPORTUNITY

‘[E]liminating helminths in infected individuals may directly impact control of other infectious diseases such as HIV. . . .’ ‘Despite WHO recommendations, school-based implementation is not universal and many helminth-infected school-age children go untreated.’

Helen L. Gerns1*, Laura R. Sangaré2, Judd L. Walson1,2,3

1 Department of Epidemiology, University of Washington, Seattle, Washington, United States of America, 2 Department of Global Health, University of Washington, Seattle, Washington, United States of America, 3 Department of Medicine, University of Washington, Seattle, Washington, United States of America

Citation: Gerns HL, Sangaré LR, Walson JL (2012) Integration of Deworming into HIV Care and Treatment: A Neglected Opportunity. PLoS Negl Trop Dis 6(7): e1738.

Editor: Simon Brooker, London School of Hygiene & Tropical Medicine, United Kingdom

Published: July 31, 2012.

Also accessible at http://www.plosntds.org/article/info%3Adoi%2F10.1371%2Fjournal.pntd.0001738

* E-mail: hgerns@uw.edu

In sub-Saharan Africa, where two-thirds of all HIV-infected individuals reside, many are now aware of their HIV infection status and millions are receiving antiretroviral therapy. In many countries in the region, new infections are declining and individuals are living longer with treatment to control their HIV infection. The infrastructure behind HIV care and treatment is vital in addressing the HIV pandemic, and similarly could be utilized to address and promote other health issues specific to persons living with HIV.

An estimated 2.1 million children are infected with HIV in sub-Saharan Africa, where multiple helminth species are also endemic [1]. Likely half of these children are co-infected with helminths [2]. The most recognized consequences of helminth infection in children include anemia, malnutrition, and impaired cognitive development, which are independent risk factors for death among HIV-infected children. Standard treatment of soil-transmitted helminth infection entails a single 400 mg dose of albendazole [3], making routine deworming of children a simple intervention that safely and affordably prevents the adverse effects of chronic helminth infection. Deworming HIV-infected children, specifically, may have a substantial impact on child health through the synergistic effects of improved nutritional status, greater control of other infectious diseases, and increased vaccine responsiveness, and therefore should be provided though HIV care services [3].

Helminth infection in HIV-infected children may impact how the host responds to infectious diseases and immunizations, indirectly through the pathway of malnutrition, as well as directly through immunologic mechanisms. Beyond nutritional deficits, helminths also induce immunosuppressive responses, creating an ideal environment for chronic helminth infection, and inhibiting the host's ability to control other diseases such as HIV [4], [5]. Clinical studies suggest that deworming HIV-infected individuals may delay HIV progression, as measured by CD4 count and HIV viral load [6]–[9]. It is plausible that in addition to improving nutritional status, eliminating helminths in infected individuals may directly impact control of other infectious diseases such as HIV.

Helminth infection may also undermine the benefits of childhood immunizations, through malnutrition, and also by diminishing immune responses to vaccines, both at the time of vaccination and at disease exposure. Population-level data show that regional variations in vaccine efficacy correlate with variations in the prevalence of enteric pathogens [10]. For example, rotavirus vaccine efficacy may be 50% higher in developed countries compared to Africa and Asia [11]. Polio eradication efforts have also been challenged by diminished efficacy of the oral polio vaccine in India as compared to the rest of the world [12]. While the distribution of soil-transmitted helminths represents only one of several factors contributing to these regional variations in vaccine responsiveness, it is a factor which can be easily targeted and controlled through routine deworming [13].

Individual-level evidence also suggests that helminth infection impacts immunologic responses to vaccines. Experimental human and animal studies have shown deworming before immunization increases protective antibody titers, while decreasing immuno-regulatory cytokines [14]–[16]. Children who failed to respond to oral poliovirus vaccination were 25% (p = 0.04) more likely to harbor infections with intestinal parasites than vaccine responders [17]. Additionally, children with ascariasis who received albendazole prior to receiving oral cholera vaccine were 88% (p = 0.06) more likely to seroconvert than children who were not dewormed [18]. Interactions that diminish responses to vaccines at the time of vaccination may also diminish immune recall of vaccines at the time of disease exposure. As HIV-infected children are more susceptible to vaccine preventable illness and death than other children [19], even after the introduction of anti-retroviral therapy [20], deworming HIV-infected children may have a measurable impact on vaccine preventable infections.

The World Health Organization (WHO) recommends annual or bi-annual school-based deworming as a cost-effective strategy to diminish the consequences of chronic helminth infection. Deworming could also be considered part of the nutritional care package for HIV-infected children, to reduce the consequences of malnutrition and anemia in HIV. Incorporating deworming into routine HIV care and treatment is an ideal way to improve the nutritional health of HIV-infected children, and may provide additional benefits. This may be particularly beneficial for children under 5 years of age, who represent 10%–20% of the 2 billion people infected with helminths worldwide [21]. Annual deworming of preschool-age children is safe and highly effective in reducing parasite prevalence and intensity, malnutrition, and risk of stunting, but a formal policy does not yet exist to target this age group [21], [22]. Because children are infected and often diagnosed with HIV while very young, preschool-aged children can easily be dewormed in HIV clinics, along with siblings, to reduce the occurrence of reinfection.

Despite WHO recommendations, school-based implementation is not universal and many helminth-infected school-age children go untreated. Children who are sick or otherwise unable to attend school may miss school-based interventions, leading to more illness and absenteeism. Children with HIV may also be less likely to receive other health services. For example, HIV-infected children are less likely to receive complete vaccination series compared to uninfected children [23]. HIV care centers are an important, and highly accessed, point of serial contact for HIV-infected children and their families [24]. However, at present they often provide a narrow range of services. In addition to integrating deworming into current HIV treatment, the integration of other necessary childhood health interventions, including vitamin supplementation, immunizations, safe drinking water (through home water filtration), and insecticide-treated bed nets, may further reduce HIV-related morbidity and mortality among these children [24].

Challenges may exist in coupling other health interventions to HIV care, but the potential benefits warrant consideration. Deworming both in schools and HIV clinics is likely justified by the high rates of recurrent infection in children and the low cost of the intervention. Finally, little evidence exists on the impact of deworming in HIV-infected children, highlighting a need for more rigorous studies. These studies should investigate the effects of helminth infection on responses to immunizations, the potential interactions between antihelminthics and HIV treatment, the optimal timing of deworming around both immunizations and ART initiation, and the impact of deworming on incidence of vaccine preventable infections.

The benefits of treating and preventing helminth infections in HIV-infected children may go beyond the improved nutritional status and cognitive development observed in all children to also include improved responses to immunizations and control of other infectious diseases. Enhanced control of neglected infectious diseases, such as helminth infections, through existing HIV care and treatment programs, may further reduce childhood morbidity and mortality in this vulnerable population.

Acknowledgments 

Dr. Noel S. Weiss is thanked for his editorial comments on this manuscript.

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Noland GS, Chowdhury DR, Urban JF, Zavala F, Kumar N (2010) Helminth infection impairs the immunogenicity of a Plasmodium falciparum DNA vaccine, but not irradiated sporozoites, in mice. Vaccine 28: 2917–2923.  

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‘[T]here is evidence of benefit for deworming HIV-1 co-infected adults.’

Walson JL, Herrin BR, John-Stewart G

Persons in resource-constrained settings are often disproportionately affected by both HIV-1 and other infectious diseases, such as helminth infections. Helminths are parasitic organisms that live within the human body. Over one-third of the world's population is infected with at least one species of helminth. Findings from some observational studies have suggested that treating helminth infections may slow the progression of HIV-1 disease. If treatment of helminth infections can reduce morbidity and mortality or delay the need for antiretroviral drugs among HIV-1-infected persons, the clinical, programmatic, and public health benefits of these effects are likely to be substantial. The results of this systematic review suggest that eradication of helminths appears to impart significant benefit to HIV-1 and helminth co-infected individuals. Further studies are warranted to determine the long-term impact of deworming and to evaluate the relative benefit of eradicating individual helminth species.

Background: 

The HIV-1 pandemic has disproportionately affected individuals in resource-constrained settings where other infectious diseases, such as helminth infections, also are highly prevalent. There are biologically plausible reasons for possible effects of helminth infection in HIV-1-infected individuals, and findings from multiple studies suggest that helminth infection may adversely affect HIV-1 progression. Since initial publication of this review (Walson 2007), additional data from randomized controlled trials (RCTs) has become available. We sought to evaluate all currently available evidence to determine if treatment of helminth infection in HIV-1 co-infected individuals impacts HIV-1 progression.

Objectives: 

To determine if treating helminth infection in individuals with HIV-1 can reduce the progression of HIV-1 as determined by changes in CD4 count, viral load, or clinical disease progression.

Search strategy: 

In this 2008 update, we searched online for published and unpublished studies in The Cochrane Library, MEDLINE, EMBASE, CENTRAL, and AIDSEARCH. We also searched databases listing conference abstracts, scanned reference lists of articles, and contacted authors of included studies.

Selection criteria: 

We searched for RCTs and quasi-RCTs that compared HIV-1 progression as measured by changes in CD4 count, viral load, or clinical disease progression in HIV-1 infected individuals receiving anti-helminthic therapy.

Data collection and analysis: 

Data regarding changes in CD4 count, HIV-1 RNA levels, and/or clinical staging after treatment of helminth co-infection were extracted from identified studies.

Main results: 

Of 7,019 abstracts identified (6,384 from original searches plus 635 from updated searches), 17 abstracts were identified as meeting criteria for potential inclusion (15 from previous review plus an additional two RCTs). After restricting inclusion to RCTs, a total of three studies were eligible for inclusion in this updated review.

All three trials showed individual beneficial effects of helminth eradication on markers of HIV-1 disease progression (HIV-1 RNA and/or CD4 counts). When data from these trials were pooled, the analysis demonstrated significant benefit of deworming on both plasma HIV-1 RNA and CD4 counts.

Authors' conclusions: 

To date, three RCTs have evaluated the effects of deworming on markers of HIV-1 disease progression in helminth and HIV-1 co-infected individuals. All trials demonstrate benefit in attenuating or reducing plasma viral load and/or increasing CD4 counts. When taken together, there is evidence of benefit for deworming HIV-1 co-infected adults. Given that these studies evaluated different helminth species and different interventions, further trials are warranted to evaluate species-specific effects and to document long-term clinical outcomes following deworming.

This record should be cited as: 

Walson JL, Herrin BR, John-Stewart G. Deworming helminth co-infected individuals for delaying HIV disease progression. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD006419. DOI: 10.1002/14651858.CD006419.pub3

• CO­LO­NI­AL­ISM IN AFRICA HELPED LAUNCH THE HIV EPIDEMIC A CENTURY AGO

Excerpted from "Tinderbox: How the West Sparked the AIDS Epidemic and How the World Can Finally Overcome it," 2012, The Penguin Press.

Published: February 28, 2012 

The Washington Post

Also at http://www.washingtonpost.com/national/health-science/colonialism-in-africa-helped-launch-the-hiv-epidemic-a-century-ago/2012/02/21/gIQAyJ9aeR_story.html

We are unlikely to ever know all the details of the birth of the AIDS epidemic. But a series of recent genetic discoveries have shed new light on it, starting with the moment when a connection from chimp to human changed the course of history.

We now know where the epidemic began: a small patch of dense forest in southeastern Cameroon. We know when: within a couple of decades on either side of 1900. We have a good idea of how: A hunter caught an infected chimpanzee for food, allowing the virus to pass from the chimp’s blood into the hunter’s body, probably through a cut during butchering.

As to the why, here is where the story gets even more fascinating, and terrible. We typically think of diseases in terms of how they threaten us personally. But they have their own stories. Diseases are born. They grow. They falter, and sometimes they die. In every case these changes happen for reasons.

For decades nobody knew the reasons behind the birth of the AIDS epidemic. But it is now clear that the epidemic’s birth and crucial early growth happened during Africa’s colonial era, amid massive intrusion of new people and technology into a land where ancient ways still prevailed. European powers engaged in a feverish race for wealth and glory blazed routes up muddy rivers and into dense forests that had been traveled only sporadically by humans before.

The most disruptive of these intruders were thousands of African porters. Forced into service by European colonial powers, they cut paths through the exact area that researchers have now identified as the birthplace of the AIDS epidemic. It was here, in a single moment of transmission from chimp to human, that a strain of virus called HIV-1 group M first appeared.

In the century since, it has been responsible for 99 percent of all of the world’s deaths from AIDS — not just in Africa but in Moscow, Bangkok, Rio de Janeiro, San Francisco, New York, Washington. All that began when the West forced its will on an unfamiliar land, causing the essential ingredients of the AIDS epidemic to combine.

It was here, by accident but with motives by no means pure, that the world built a tinderbox and tossed in a spark.

The chimps of Cameroon

Many simians, such as gorillas and monkeys, can carry a virus that resembles HIV. But scientists now know that HIV-1 group M was born from a virus circulating among a community of chimpanzees concentrated in Cameroon, a sprawling country with bustling Atlantic Ocean ports, populous highlands, and a lightly developed southern region where relatively few people live even today. This was home to the chimps.

Finding a more exact location took a remarkable degree of scientific ingenuity. An international research team led by Beatrice Hahn of the University of Alabama at Birmingham and Paul Sharp of the University of Edinburgh developed an elaborate project that involved searching for the simian virus in chimp feces collected across a vast swath of southern Cameroon.

To find a strain of the simian virus that was, on a genetic level, essentially indistinguishable from the most lethal form of HIV, the research team set up 10 stations across the region. Two of the stations were in the particularly remote southeastern corner of the nation, as far as possible from major population centers.

Ivory and rubber

Powering the big bang was the burgeoning trade of colonial Africa.

It was in these two stations where Hahn and Sharp’s team discovered samples of the simian virus that was almost a perfect match for the HIV-1 group M that eventually killed tens of millions of humans.

This discovery, published in the journal Science in 2006, intensified the quest for a birth date for the virus. Again, genetic research offered the key clues.

Scientists had long known that a blood sample, preserved from 1959, showed that HIV had been circulating in Kinshasa, the capital of Congo, for several decades before the virus first drew international attention in the 1980s. In 2008, evolutionary biologist Michael Worobey sharpened that picture when he reported in the journal Nature the discovery of a second sample of the virus, trapped in a wax-encased lymph node biopsy from 1960.

By comparing these two historic pieces of virus and mapping out the differences in their genetic structures in his lab at the University of Arizona, Worobey determined that HIV-1 group M was much older than anyone had thought. Both samples of the virus appeared to have descended from a single ancestor at some time between 1884 and 1924. The most likely date was 1908.

Taken together, these two discoveries offered the clearest clues to the birth and early life of the epidemic.

Not far from where HIV-1 group M was born was a major river, the Sangha, flowing toward the heart of Central Africa. This section of the Sangha was not ideal for navigation because of its ribbons of sandbars and the dense vegetation along its banks.

In the especially treacherous middle section, near where Hahn and Sharp’s team found the viral ancestor of HIV, few major human settlements ever developed. But there were numerous communities on the Sangha’s more accessible stretches. And due south, past riverside trading towns, was the mighty Congo River itself, the superhighway of Central Africa.

Once the virus made the jump from chimp to human, a single infected person could have carried HIV down the Sangha, onto the Congo River and into Kinshasa. The Belgians had founded the city in 1881, during what historians call “The Scramble for Africa,” when colonial powers carved up the continent into areas of influence. By the early 20th century Kinshasa, then called Leopoldville, was the biggest city in Central Africa, fueled by the dizzying growth of trade with the outside world.

A final, powerful bit of evidence supported the theory that Kinshasa lay at the heart of the epidemic’s early movements.

Scientists studying HIV-1 group M already had found many related varieties, what scientists call subtypes, each with slightly different genetic structures and paths through the world. One, scientists discovered, had traveled east from Kinshasa toward Lake Victoria. One went south to Zambia, Botswana and South Africa. One hopped all the way across the ocean to Haiti, then to the United States and Europe.

Many others traveled not very far at all, staying in the Congo Basin. But as scientists plotted out the genetic histories of these varieties and built an extensive family tree for HIV, they all appeared to have spread from a single explosion, a big bang of the AIDS epidemic: Ground Zero was Kinshasa.

Ivory may seem a touch quaint today, but in its heyday it was seen as beautiful, versatile and essential to many everyday products. It was used to make billiard balls, jewelry and cutlery. Furniture makers incorporated it into their cabinets, artists into their statues. Bagpipe makers used ivory for mounts, ferrules, buttons and mouthpieces.

When supplies of ivory gradually grew short, as colonial agents killed the once plentiful elephants by the thousands, rubber took its place as the economic lifeblood of colonialism in the Congo Basin. The first inflatable rubber tires for bicycles became popular in the 1890s. Mass production of cars soon spiked demand for rubber tires again.

The only obstacle to European companies’ reaping huge profits was that collecting ivory and rubber required massive amounts of labor. Getting ivory from an elephant meant stalking the animal, killing it and cutting off its tusks. Getting rubber from vines required slashing them, collecting the oozing white sap and drying it — sometimes on the collector’s own skin.

The solution to the manpower demands soon became obvious. Colonial powers created what was essentially slavery: cheap muscle at the point of a gun.

This approach was not confined to collecting ivory and rubber. These industries created tremendous new needs for infrastructure to get goods to oceangoing ships along the Atlantic coast. That meant African porters had to carry goods and supplies anyplace the steamboats couldn’t reach.

Workers were needed to build railroads, trading stations, dormitories. And somebody needed to operate the steamboats, load the railroad cars, carry the tusks or gobs of rubber in from the jungle. When workers became unruly, the colonial companies deployed heavily armed soldiers to keep the cogs of these vast enterprises moving.

All these roles were filled by Africans, many imported from villages hundreds or even thousands of miles away. African life here was beyond cheap. It was disposable. Contemporary accounts by journalists and missionaries tell of colonial officials across the Congo Basin ordering mass slaughters and the torching of restive villages while creating forced settlements that resembled nothing so much as concentration camps.

The role of African porters

In December 1895 German colonial authorities heard reports that Cameroon’s southeastern corner contained fabulously rich ivory and rubber stocks awaiting exploitation.

The Germans soon after gave authority to a colonial company to take control of the region by force. Over the next four years they extended their power all the way through southeastern Cameroon and established a trading station on the Ngoko River about 75 miles upstream from where its waters merged with the Sangha. In the wedge of land defined by these two rivers, HIV either had just been born or soon would be.

The trading station was called Moloundou, and a busy town remains there today. But at the time it was almost unimaginably remote. Few human settlements had developed among these forbidding forests. And there were only two practical ways out: by steamship down the Ngoko to the Sangha and on to the Congo River; or overland by foot to the Atlantic.

The river route was the easier of the two, and steamships transported the bulk of the ivory and rubber collected in southeastern Cameroon. But overland routes were necessary to connect Moloundou with other trading stations and inland areas rich with rubber and ivory.

For these journeys the bounty was borne by Africans who carried loads averaging 55 pounds each. At the peak of the foot traffic that would develop between inland areas and the coast, the busy way station recorded more than a thousand porters passing by on a typical day.

Trade routes, disease routes

Ominously, something else followed the rubber trade through Cameroon: disease. Sleeping sickness, smallpox and skin infections were the most obvious.

Colonial authorities attempted mass inoculation campaigns for smallpox and set up quarantine zones that restricted where the porters were allowed to travel. But even so, the diseases spread.

Among them was syphilis, which arrived with the Europeans. In just a few years it reached epidemic proportions along porter routes and riverside trading posts in Cameroon and throughout the Congo Basin. It’s impossible now to determine how much of this spread resulted from rapes as opposed to other kinds of encounters, but it’s clear that colonial commerce created massive new networks of sexual interactions — and massive new transmissions of infections. (In later decades, transmission through the reuse of hypodermic needles in medical care probably had some role in HIV’s spread as well.)

So HIV’s first journey looked something like this: A hunter killed an infected chimp in the southeastern Cameroonian forest, and a simian virus entered his body through a cut during the butchering, mutating into HIV.

This probably had happened many times before, during the centuries when the region had little contact with the outside world. But now thousands of porters — both men and women — were crossing through the area regularly, creating more opportunities for the virus to travel onward to a riverside trading station such as Moloundou.

One of the first victims — whether a hunter, a porter or an ivory collector — gave HIV to a sexual partner. There may have been a small outbreak around the trading station before the virus found its way aboard a steamship headed down the Sangha River.

For this fateful journey south, HIV could have ridden in the body of these first victims, or it could have been somebody infected later: a soldier or a laborer. Or it could have been carried by a woman: a concubine, a trader.

It’s also possible that the virus moved down the river in a series of steps, maybe from Moloundou to Ouesso, then onward to Bolobo on the Congo River itself.

There might even have been a series of infections at trading towns along the entire route downriver. Yet even within these riverside trading posts HIV would have struggled to create anything more than a short-lived, localized outbreak.

Most of this colonial world didn’t have enough potential victims for such a fragile virus to start a major epidemic. HIV is harder to transmit than many other infections. People can have sex hundreds of times without passing the virus on. To spread widely, HIV requires a population large enough to sustain an outbreak and a sexual culture in which people often have more than one partner, creating networks of interaction that propel the virus onward.

To fulfill its grim destiny, HIV needed a kind of place never before seen in Central Africa but one that now was rising in the heart of the region: a big, thriving, hectic place jammed with people and energy, where old rules were cast aside amid the tumult of new commerce.

It needed Kinshasa. It was here, hundreds of miles downriver from Cameroon, that HIV began to grow beyond a mere outbreak. It was here that AIDS grew into an epidemic.

Laying the scientific story alongside the historical one offers one final revelation. In the 1920s, as railroads became widely available, the Sangha River’s value as a steamship route dwindled sharply. Global rubber prices also collapsed. The pace of human movement through the region eased.

So the improbable journey of the killer strain of HIV was feasible for only a few hectic decades, from the 1880s to the 1920s. Without “The Scramble for Africa,” it’s hard to see how HIV could have made it out of southeastern Cameroon to eventually kill tens of millions of people. Even a delay might have caused the killer strain of HIV to die a lonely death deep in the forest.

From “Tinderbox” by Craig Timberg and Daniel Halperin. Reprinted by arrangement with The Penguin Press, a member of Penguin Group (USA) inc. Copyright © Craig Timberg and Daniel Halperin, 2012. Timberg, a former foreign correspondent in Africa, is acting national security editor of The Washington Post. Halperin was a senior HIV prevention adviser in the U.S. government’s global AIDS program and is now an epidemiologist at the University of North Carolina.