Carolyn Colwell

An unknown South African boy may gain fame as the source of key clues to quelling the HIV virus. The announcement this summer of the boy’s 8-plus year survival after only 40 weeks of antiretroviral therapy (ART) in infancy has been heralded as a breakthrough.

The case strengthens hope for sparing HIV-infected children “the burden of life-long therapy and the health consequences of long-term immune activation” through a brief treatment period beginning in infancy, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID), said.

The National Institutes of Health (NIH)-funded study showed how the currently 9-year-old boy received seemingly successful ART treatment among 252 HIV-infected infants. Infants were treated from between 6-12 weeks old up until the age of 2 years old. The 125-patient control group in the study had ART initiation delayed for a median of 40 weeks.

The surviving child had started ART 2007, at 32 days old. His high viral load was suppressed after 40 weeks of therapy.

Avy Violari, MD — co-leader of the study, head of pediatric research at the Perinatal HIV Research Unit at University of the Witwatersrand in Johannesburg, South Africa &mdash; said, to her knowledge, it was the first reported case of “sustained control of HIV in a child enrolled in a randomized trial of ART interruption following treatment early in infancy.”

Perhaps due to its rarity, the explanation for the child’s survival versus other trial patients is currently unknown. Caroline Tiemessen, PhD, head of cell biology at the Centre of HIV and STIs of the National Institute of Communicable Diseases (NICD) in Johannesburg, said further analysis of the survivor may bring a stronger understanding as to “how the immune system controls HIV replication.”

David W. Rosenthal, DO, PhD — Medical Director for the Center for Young Adult, Adolescent and Pediatric HIV for Northwell Health in New York &mdash; believed that a combination of genetic factors and unique immunological marker expressions “together may make a difference in this child.”

Although, according to the NIH, there have been at least 2 other long-term HIV survivors to have received ART at an early age, their treatment differed from the South African boy’s. His short dose period and extended period of time removed from ART treatment makes his case unique, Rosenthal said.

He, and other survivors, may hold genetic or immunological clues to suppressing the once-lethal virus.

“We ought to learn as much as we can about what makes these persons unique so we can find more therapeutic options that can be expanded to a larger population,” Rosenthal said.

Press releases were provided by NIH and the University of the Witwatersrand.

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South African child with HIV reaches 8-plus year survival after only 40 weeks of antiretroviral therapy in infancy.

Clues Found to Long-Term HIV Suppression

In 2014, practically half of HIV patients in the US were in remission, according to the latest data recently released by the CDC. That statistic may be only half the story.

While the national split is a significant jump from previously reported rates, the degrees of the success vary in different parts of the country, Barry S. Zingman, MD, Medical Director, AIDS Center, Montefiore Health System, told 

At his Center for Positive Living/ I.D. Clinic in The Bronx, NY, among the 3,300 HIV patients in treatment, the viral suppression rate is greater than 85%, and going up every year. Zingman said many other sites "around the country are seeing viral suppression rates in the 80s and 90s and that’s gratifying to see."

By contrast, the Centers for Disease Control and Prevention (CDC) statistics show some states such as Virginia and South Dakota only 34.3% and 40.4% of people with HIV 13 years of age and older, respectively, have achieved viral suppression, Zingman said.

The whole Montifiore system tests about 50,000 people a year in The Bronx and the southern part of nearby Westchester County, Zingman explained. It finds about 150 HIV infections annually. Overall, there are 24,000 people in The Bronx carrying the HIV virus, which means this area has more HIV cases than 41 states.

Increased testing has been a major US goal for increasing diagnosis, care, and the rate of suppression. Whether that happens depends to a large degree upon the characteristics of an area where someone lives — income, jobs, access to care.

People retaining medication regimens and continued care is crucial, Zingman said. Because Medicaid is the key insurer in the US, Mediciad expansion states "have shown greatly increased rates in viral suppression compared with the non Medicaid expansion states."

“If people can get insurance, they want to take care of this," Zingman said. "They know these are life saving therapies that we have.”

The improvement in anti-retroviral therapies (ART) for HIV is also a source of increased HIV suppression among the 1.1 million people in the US living with HIV, Zingman suggested. The doubt about whether ART can suppress viral load has been replaced with certainty in the last 5 years. In addition more ART regimens can involve only one pill a day and side effects are significantly lower than 7 or 8 years ago.

As the CDC has highlighted, there are still miles to go get consistent care for some population groups. For example, only 27% of young people with HIV had the virus suppressed, according to the CDC analysis of the latest data.

Due to "more unstable lives," reaching young people with HIV has been a persistent issue, Zingman said.

“They are a particular focus for engaging them in care and keeping them in care, and enabling them to stay on medication better, and they are also the group most at risk for transmitting HIV to others," Zingman said.

The degree of the success for HIV remission vary in different parts of the country.

More Patients With HIV Living in Remission

About one-third of patients with HIV with low viral loads tempted fate and avoided taking medications despite recommendations, according to a 10-year University of North Carolina (UNC) study.

The mass prolonged delay in antiretroviral treatment (ART) among patients necessitate scrutinization of the current guidelines for HIV therapy, the study’s authors noted. 

Joseph Enron, MD, professor of medicine at the UNC Chapel Hill’s School of Medicine, discovered with a team of researchers that lower-viral load patients delaying therapy may still persist “despite clear evidence of the benefits of immediate therapy initiation."

With the increasing ability of ART to put HIV into remission, federal guidelines since early 2012 have suggested that anyone who tests positive for HIV begin therapy immediately in order to reduce disease progression and reduce transmission. Prior to that time, guidelines made moderate-to-strong recommendations to start ART. The UNC research covered the period of January 2003 to December 2012, so that most of the patients in the study were not covered by the most recent federal guidelines.

The UNC research was based on data of 4,907 HIV positive patients  for whom treatment was strongly-to-moderately recommended, enrolled in 8 HIV clinics across the country during the set time frame. All of the test subjects had not previously been on ART.

Viral load is measured by the number of HIV RNA (viral load = 10,000 RNA per mL of blood; high load = 100,000). At the beginning of their participation, patients with viral loads of less than 10,000 had a .36 higher risk ratio of being more likely to delay ART than those with a viral load of at least 100,000. 

Across the entire study period, 26.3% of those with viral loads of 10,000 or less did not start ART, and 37.3% of those with viral loads of at least 100,000 had also not begun ART.

To be included in the study, patients needed infection-killing white blood cell (CD4) counts of 350 cells/mm or below. A normal count is considered to be in the range of 500 to 1,500. AIDS may be diagnosed when that count drops below 200. 

Those with a CD4 count of at least 200 cells/mm at the beginning of their participation in the study were 1.3 as likely to delay ART than those with counts of less than 200. From 2003 through 2012, 54.6% of the participants with CD4 counts less than 200 did not initiate ART.

While a low viral load over the course of the study was the most statistically significant factor in delaying ART, an AIDS diagnosis also played a role. In the group that started in 2003 to 2007, 64.3% did not begin ART. In the group that started participating in the study in the 2008 to 2012 period, 74.1% with AIDS diagnoses were not initiators.

 “Though guidelines also recommended ART initiation for patients with an AIDS diagnosis, it is possible that our findings that a prevalent AIDS diagnosis was associated with delayed ART initiation could have resulted from a lower engagement in care,” according to the study.

Enrollment date was the only demographic factor that appeared to affect the willingness to start ART, according to the study.

“For example, for each one year increase…in enrollment date, patients were 0.94 times (95% CI:0.92, 0.97) as likely to delay ART initiation,” researchers wrote.

Unexpectedly, demographic characteristics such as gender, age, race/ethnicity, and HIV risk factors such as reported male-to-male sexual contact and injection drug abuse were not significantly associated an ART delay. Enrollment date was the only demographic factor that appeared to affect the willingness of study participants to start ART, the study said. “For example, for each one year increase…in enrollment date, patients were 0.94 times (95% CI: 0.92, 0.97) as likely to delay ART initiation,” the study explained.

Six percent of the study participants who did not initiate ART died within 2 years of enrolling. In 2014 in the US, 12,333 people died of AIDS-related causes, according to the US Centers for Disease Control and Prevention. ART has been credited with increasing longevity for people who are HIV positive, making HIV more of a chronic condition than a terminal one.

“Despite the known benefits of early antiretroviral therapy initiation, a lower viral load measurement may continue to be an important clinical characteristic in the more recent era with current ART initiation guidelines,” researchers wrote. “These findings provide a target for closer monitoring and intervention to reduce disparities in HIV care.” 

Risk factors for delayed antiretroviral therapy initiation among HIV-seropositive patients

Prolonged delay in antiretroviral treatment among patients necessitate scrutinization of the current guidelines for HIV therapy.

Some HIV Patients With Low Viral Load Forgo Treatment

Inexpensive, effective, and long-lasting medications are essential if the scientific community wants to successfully treat the more than 36 million people worldwide living with HIV, according to a recent editorial in a global health journal.

Longer-acting HIV medications could solve problems with adherence, reduce costly laboratory tests to monitor their efficacy, and bring down drug costs—a major factor in middle- and low-income countries where HIV is most prevalent.

“With several highly potent agents in the pipeline and a healthy proliferation of many promising technologies for long-acting delivery, the prospects for very long-acting ARVs [anti-retrovirals] for treatment and prevention have never been brighter,” said Matthew Barnhart MD, MPH,  medical officer for the US Agency for International Development and associate editor of Global Health: Science and Practice.

Barnhart outlined and described 5 types of drug developments that put HIV treatment on the threshold of a breakthrough:

A combination of two AVRs, ViiV's cabotegravir (an integrase inhibitor) and Janssen's rilpivirine (a non-nucleoside reverse transcriptase inhibitor) is in phase 3 trials. The combination is a monthly or every-other-month maintenance medication for people who have achieved non-detectable viral loads on standard ARV oral protocols. Investigators are also looking at cabotegravir alone as an every-other-month injection for HIV prevention.

The combination, however, has limitations in terms of residual effects if someone stops taking it, as well as in administration, including uncomfortable injections in the buttocks that require costly staff time.

These include the capsid inhibitor GS-CA1, a new class of AVRs, and new nucleoside/tide reverse transcriptase inhibitors (NRTIs). Two of these NRTIs, EFdA (GS-9131) and TAF (tenofovir alafenamide fumarate), have the advantage of long half-lives that allow them to become “effectively trapped within cells, thereby amplifying their levels and potency,” Barnhart explained in his editorial. TAF, already approved as an oral medication, is being investigated as a drug that can be released from a long-lasting implant. Gilead’s GS-CA1 is in the pre-clinical stage, Merck’s EFdA is in phase 1, and Gilead’s TAF as an implant is in phase 1.

Two large trials are investigating bnAbs called VRC01 as a medication for HIV prevention. It would be impractical, however, because VRC01 would have to be given intravenously. Combinations of other antibodies show potential for 6-month duration and administration by subcutaneous injection, the editorial read.

Long-acting AVRs could have a duration of up to a year in an implant, but Barnhart questioned how practical it would be to require annual removal and replacement of the implant. He instaed proposed biodegradable or refillable implants, which would require new implant designs.

Implants under development release AVRs through a membrane so that the reservoir gradually empties after the outer coating biodegrades and consequently avoids the potential problem of the device dumping medication when it wears out. A refillable implant has been conceived using refillable nanochannels that would release more than one type of AVR at potentially high doses, the editorial said.

Easier-to-use subcutaneous injection devices that allow self-administration or administration by low-level community health workers have already been developed for use with other drugs. Another option would be micro-needle patches — these could be used with new drugs that only need low doses and volumes that could be used quarterly. Their implementation hinges on the ability to manage the cost of manufacturing the injection devices.

Barnhart stressed that cost is a major consideration when designing treatments for use in middle-to-low income countries. In the past, there have been large gaps between the time new ARV agents were introduced in affluent countries and when they became available in low- and middle-income nations.

To narrow that gap, requirements for products in resource-limited settings may need to be more stringent, the editorial read. For example, the cost of manufacturing, safety during pregnancy, and compatibility with tuberculosis medications need to be considered before new drugs and treatment systems can be useful in the less affluent nations.

“If the current promise is fulfilled, long-acting AVRs can be the keystone in finally controlling the HIV epidemic, and many of the technological and scientific advances made in the process will have application to combating other global healthy scourges, multiplying the long-term impact of these efforts,” Barnhart concluded.

Barnhart said that the opinions expressed in his editorial are his own and not of USAID.

Long-acting HIV medications could solve problems with adherence, reduce costly laboratory tests to monitor their efficacy, and bring down drug costs.

Top 5 HIV Drugs in the Pipeline

By impairing brain connectivity, an HIV infection may affect cognition in young patients, according to a recent imaging study.

“Collectively, the results support a model of diffuse network changes in young HIV positive individuals with limited or no treatment history and corresponding cognitive dysfunction,” the study’s senior author, Robert H. Paul PhD (pictured), director of the University of Missouri’s Institute of Mental Health, and his co-authors wrote.

The researchers used diffusion MRI-based tractography and graph-theoretic approaches to gain insights into communication between regions of the brain. The team discovered that changes in the organization of white matter in the young HIV positive patients was related to cognitive deficits detected by neuropsychological testing.

Weaker connectivity in the brains of the HIV positive test subjects correlated with significantly poorer learning/recall. Network global connection strength was measured at 385.99 standard deviations in the HIV positive group and 312.58 in the HIV negative sample. This difference had a P value of .006. There also were clinically significant differences in network global clustering co-efficient and global characteristic path length, which were other metrics for connectivity, according to the study. Psychomotor/processing speeds, executive functioning, fine motor skills and dexterity, and visuospatial skills did not appear to be affected.

These findings “were not significantly related to HIV clinical status (CD4 cell count and viral load,” the study added.  “It is extremely rare to detect any changes in brain structure and function in a population of young adults unless there is a serious neurological disease or condition present,” Christopher Pawela PhD, the editor-in-chief of the journal, 

, said in a May 10 press release. “The fact that the authors were able to detect changes in such a resilient young population gives credence to the hypothesis that HIV infection is associated with brain alterations and corresponding abnormalities in cognitive abilities.”

The study explained that neuronal loss and injury in HIV are believed to be caused in part by inflammation, which occurs soon after the virus infects the central nervous system. The infection then triggers several inflammatory and neurotoxic processes.

“These injuries are distributed widely throughout the brain and correspond to white matter damage as well as cognitive impairment, the study added.

Other research has shown that the HIV virus crosses the blood-brain barrier about 8 days after seroconversion and before symptoms of immune dysfunction or cognitive dysfunction is apparent.

“Despite the efficacy of combination antiretroviral therapy (cART) in reducing viral load, current treatments do not appear to prevent or reverse existing brain damage.”

The test subjects were 29 HIV positive and 16 demographically matched HIV negative individuals. The mean age in the HIV positive group was of 25.9 and their ages ranged from 18 to 45. Men represented 17% of the HIV positive sample and 31% of the HIV negative sample.

The mean month of infection was 9.33, and 83% of these participants had not yet started treatment or had begun it within 3 months before joining the study. The HIV positive patients were selected from a group in pre-treatment counseling at HIV clinics in Cape Town, South Africa. Patients, whose cognition potentially could be affected by psychiatric and neurological conditions, head injuries, infections, and current substance abuse, were excluded from the sample.

A National Institutes of Health grant had finances the study. Co-authors came from the University of Missouri St. Louis, Washington University, the University of Southern California, Brown University, the University of Cape Town, and the Missouri Institute of Mental Health. “Topical Organization of Whole-Brain White Matter in HIV Infection” was published in the March 1 issue of 

HIV infection may affect cognition in young patients.

Brain Connectivity Inhibited in HIV-Positive Youth

Young, HIV-positive mothers can experience better health if they continue antiretroviral treatment postpartum, according to a new, multi-racial study conducted in 8 countries.

“The data from this randomized trial provide further evidence of the benefits of continuing antiretroviral therapy [ART] after delivery in women in early stage HIV,” the lead author, Judith S. Currier MD, MPH (pictured), associate director of the Center for AIDS Research and Education (CARE) at the David Geffen School of Medicine at UCLA and a professor of medicine said in a press release.

The research by Currier and her international colleagues reportedly was the first randomized controlled study on the benefits of ART for young mothers with early HIV infections. The biggest benefit for the women continuing the ART regimen was a 50% reduction in what the World Health Organization (WHO) classified as stage II and III clinical events, according to the study. Stage II events can include recurrent oral ulcerations, chronic diarrhea, persistent respiratory infections, and fungal nail infections.

Severe weight loss, persistent fever, pulmonary tuberculosis, and recurrent bacterial infections such as pneumonia, Kaposi sarcoma, are among the stage III events. There were 2.08 stage II and III events per 100 patient year (py) in the test group that continued ART and 4.36 events per 100 py in the group that discontinued ART after delivery. At the start of the 2.3-year study, 98 of the continuing group and 99% of the discontinuing group were in WHO stage I, which symptomatically can range from asymptomatic to persistent respiratory infections.

Less than 10% of the women in the discontinued group had CD4 T-cell counts drop below 350, while only 4% of the women who continued ART had a similar drop.

“This low rate of clinical progression observed in those randomized to discontinue ART post partum also provides some reassurance for women who cannot become virologically suppressed on currently available ART, due to toxicity or tolerability or, who require observation off ART due to complex multifactorial issues that preclude adherence,” the study authors wrote.

“These findings demonstrate a very low level of AIDS events among young women as compared to rates previously reported among studies that included populations who were older,” the authors added.

It explained that difference could be due to the higher CD4 T-helper cell counts among the study’s participants. At the beginning of the study, the median CD4 count was 696, a count of 200 or less can be a sign of entering stage III.  Ninety-four percentage of the cohort had entry level HIV-1 RNA < 1000 copies. The research also looked at compliance with antiretroviral therapy — 15% of those assigned to the ART group prematurely stopped treatment.  

“This study highlights the need to develop better ways to improve adherence to long-term ART in this vulnerable population,” Currier added in the same press release. “Overall, serious clinical events were rare among young HIV-positive post-partum women with high CD4 cell counts. Continued ART was safe and was associated with halving of the rate of WHO 2/3 conditions. Virologic failure rates were high, underscoring the urgent need to improve adherence in this population,” the study concluded.

The study’s cohort included 1652 women from Argentina, Botswana, Brazil, China, Haiti, Peru, Thailand and the US with a median age of 28. The racial breakdown was 28% black African, 25% Asian, and 15% Caucasian. Prior to delivery median ART exposure was 19 weeks.

Lopinavir/ritonavir plus tenofovir/emtricitabine was the preferred ART regimen. The study, “Randomized trial of stopping or continuing ART among postpartum women with pre-ART with CD4 > 400 cell/mm,” appeared in the May 10 issue of 

Continuing ART post-delivery shows benefits in women with early stage HIV,