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Dual Maintenance Therapy With Lamivudine Viable Option
July 16, 2017

A boosted protease inhibitor (PI) combined with lamivudine is a viable maintenance therapy for those who are already virally suppressed, a clinical trial published in The Lancet HIV found.
The trial compared the boosted PI-lamivudine combination to boosted PI monotherapy in 265 people who had undetectable viral loads. Most participants were women, and almost all had the M184V mutation, which confers resistance to lamivudine and is common in Africa.
The monotherapy arm was discontinued after 48 weeks because 33 of the 133 people in this arm experienced treatment failure, compared to four of the 132 people in the lamivudine group. Given the lack of regular viral load monitoring in many low-income settings, study authors do not recommend monotherapy as a low-cost maintenance strategy.
“Dual therapy with boosted protease inhibitor and lamivudine in stable HIV-1-infected patients on second-line [antiretroviral treatment] could be considered as an alternative to triple therapy for selected patients, even despite the presence of M184V mutation at first-line failure,” the study authors concluded.

 

 

 

 

HIV-positive women with cytomegalovirus likelier to pass virus that causes AIDS to infant

July 16, 2017

University of California, Los Angeles (UCLA), Health Sciences

HIV-positive women with cytomegalovirus, or CMV, in their urine at the time of labor and delivery are more than five times likelier than HIV-positive women without CMV to transmit HIV, the virus that causes AIDS, to their infants, according to a UCLA-led study. The research also found that they are nearly 30 times likelier to transmit cytomegalovirus to their infants.

Dr. Karin Nielsen, a professor of clinical pediatrics in the division of infectious diseases at the David Geffen School of Medicine at UCLA, is the senior author of the study, which was published in the journal Clinical Infectious Diseases.

“The findings were surprising because prior studies in healthy pregnant women have not shown an association between CMV detection in urine, or even cervical secretions, and congenital CMV infection,” Nielsen said.

The research also found that women who had gonorrhea when they gave birth were nearly 20 times more likely to pass CMV on to their infants. People with healthy immune systems can stave off illness from the virus, but babies infected through their mothers and people with weakened immune systems, such as those with HIV, can experience serious health problems.

CMV can impair fetal growth, and babies born with the virus can have damage to the brain, liver, lung and spleen, as well as hearing loss. People who are otherwise healthy usually do not experience any symptoms, but it can cause fever, sore throat, fatigue and swollen glands. In people with compromised immune systems, however, CMV can affect the eyes, lungs, liver, esophagus, stomach and intestines, according to the Centers for Disease Control and Prevention.

The researchers evaluated 260 pairs of mothers and infants — 222 from the Americas and 38 from South Africa — who were enrolled in a perinatal study by the National Institute of Child Health and Human Development. None of the mothers had used antiretrovirals prior to labor.

After testing the mothers’ and infants’ urine for CMV, the researchers found that:

  • 2 percent of the women had detectable CMV and 3.8 percent of the infants had the virus.

  • 8 percent of women with detectable CMV had infants with the virus, as opposed to 2.1 percent of women who did not have detectable CMV.

  • 2 percent of women with detectable CMV transmitted HIV to their infant, compared with 8.1 of those who did not have detectable CMV.

Among the study’s limitations: The sample size was determined by the availability of urine samples from the mothers, and women in the overall study from which data was drawn were diagnosed with HIV at the time of labor and delivery, so results of the UCLA-led research are not applicable to pregnant women with HIV who are on antiretroviral treatment during pregnancy.

Still, the study “underscores the importance of controlling HIV-infection during pregnancy through use of antiretrovirals in the prevention of both CMV and HIV transmission from mothers to infants,” said Dr. Kristina Adachi, a postdoctoral researcher in pediatric infectious diseases in the UCLA department of pediatrics and the study’s lead author.

 

Journal Reference:

  1. Kristina Adachi, Jiahong Xu, Bonnie Ank, D. Heather Watts, Lynne M. Mofenson, Jose Henrique Pilotto, Esau Joao, Breno Santos, Rosana Fonseca, Regis Kreitchmann, Jorge Pinto, Marisa M. Mussi-Pinhata, Glenda Gray, Gerhard Theron, Mariza G. Morgado, Yvonne J. Bryson, Valdilea G. Veloso, Jeffrey D. Klausner, Jack Moye, Karin Nielsen-Saines. Cytomegalovirus Urinary Shedding in HIV-infected Pregnant Women and Congenital Cytomegalovirus InfectionClinical Infectious Diseases, 2017; DOI: 1093/cid/cix222

 

 

 

 

 

HIV drug resistance testing not a priority for resource-limited settings, trial finds

Keith Alcorn

July 16,  2017

Resistance testing is unlikely to improve the effectiveness of second-line HIV treatment in resource-limited settings and the introduction of routine HIV drug resistance testing is not a high priority, investigators from a large international study have concluded in a report in the journal The Lancet HIV.

Instead, their findings and those of other recent research reports point to the need to prioritise adherence support, the scale-up of viral load testing and prompt action when test results show a rebound in viral load.

The findings, from the EARNEST study of second-line antiretroviral treatment in Africa, show that even when people have predicted resistance to two of the three drugs in their second-line drug combination, they are still highly likely to achieve and maintain an undetectable viral load, suggesting that the drugs still exert enough activity to prevent viral rebound.

Resistance testing in lower-income settings

Resistance testing is used in higher-income settings to select drugs for second- or third-line treatment, especially those of the nucleoside analogue class. Resistance testing plays less of a role in choosing second-line treatment regimens nowadays because the greater range of available drug classes makes it easier to put together a regimen of active drugs. Determining a patient’s drug resistance profile remains critical after the failure of a second- or third-line drug regimen.

In lower-income settings, resistance testing is used largely for surveillance, to check if drug-resistant virus is being transmitted and to determine the prevalence of resistance to various drugs. Resistance testing requires laboratory conditions that may exist only in central hospitals or research laboratories, so it is not carried out routinely. The cost of a resistance test is also a major barrier to routine use.

The World Health Organization (WHO) has advised that resistance testing is not essential in lower-income settings, and that for the time being, the risk of drug resistance can be monitored at national level by using five early warning indicators: how many people pick up medication on time; how many people are retained in care, and how many are virally suppressed, 12 months after starting treatment; drug stock-outs; and, the proportion of people on treatment who get a viral load test (coverage).

If these measures began to show a rising risk of transmissible drug-resistant virus, countries would be urged to consider changing treatment regimens or taking other steps to minimise the impact of resistance. WHO is drawing up guidance on how to respond to a rise in drug resistance this year.

The EARNEST study and second-line treatment

The EARNEST study compared three approaches to second-line antiretroviral treatment in sub-Saharan Africa. The study compared switching to a ritonavir-boosted protease inhibitor and two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs), to a boosted protease inhibitor and the integrase inhibitor raltegravir, or protease inhibitor monotherapy following 12 weeks of induction therapy with raltegravir and boosted protease inhibitor.

The study found no significant difference in viral suppression rates between the protease inhibitor + NRTI group and the protease inhibitor + integrase inhibitor group, but found protease inhibitor monotherapy to be inferior to both.

In a further analysis, study investigators have now looked at the impact of having active NRTIs – drugs to which there is no evidence of resistance – in the second-line regimen. The analysis looked at 391 of the 426 people who had received NRTIs in the study and whose baseline resistance data available. On the basis of detectable resistance mutations, the researchers predicted which drugs would be active in the study population. Fifty-nine per cent were predicted to have no active NRTIs available. In 77% of these people, their second-line regimen consisted of tenofovir and lamivudine or emtricitabine. Thirty-three per cent were predicted to have one active drug available, and in 88% of these people, the second-line regimen consisted of tenofovir and lamivudine or emtricitabine.

After almost three years of follow-up, 89% of those receiving a boosted protease inhibitor and no predicted-active NRTIs had a viral load below 400 copies/ml, compared to 81% of those who received a boosted protease inhibitor and raltegravir (both of which should have been active drugs)(p = 0.02). There was no significant difference in viral suppression between people who received one or no active NRTIs (81% vs 89%, p = 0.30). Furthermore, multivariate analysis showed that greater evidence of drug activity (measured by a drug susceptibility score) was associated with a reduced likelihood of viral suppression (odds ratio 0.61, 95% CI 0.46-0.81, p = 0.001).

The findings are surprising but the researchers say they are confident that their findings are robust, due to the large number of participants and the length of follow-up.

A lack of employment was more strongly associated with lack of viral suppression (OR 0.39, 95% CI 0.21-0.72, p = 0.003). So too were non-adherence and higher baseline viral load, after adjusting for other confounding factors.

The researchers say that drugs with predicted resistance are probably still having an effect, for example by prolonged concentrations in cells and because of the impact of some NRTI resistance mutations on HIV’s ability to copy itself accurately, without mutations. The development of these NRTI mutations may stop protease inhibitor mutations from emerging, the authors speculate.

Implications

The researchers say that selecting NRTIs that are well-tolerated and easy to take might have more impact than routine resistance testing. They urge the need for “critical thinking around the benefits to be gained, if any, before new elements of care are introduced into the public health approach, even if they are considered as standard practice in high-income settings.”

Recently published research from a trial conducted in West Africa, and findings from a study of once or twice-daily dosing in sub-Saharan Africa, India and Brazil, show that drug resistance in both trials was strongly associated with high viral load after failure of first-line treatment. In the second study (PEARLS), just over half of people with one viral load measurement over 1000 copies/ml went on to resuppress their viral load after adherence counselling.

Researchers on the PEARLS study found that a scoring system based on weight, age, time on treatment and the degree of viral rebound would result in only 0.5% of people with rebound being switched to a new regimen unnecessarily. However, the sensitivity of this scoring system was low (28%), which means that around seven out of ten people with drug resistance would experience a delay in switching if the scoring system alone were used. The research group says that its scoring system will allow some people to be switched immediately, without the need for confirmatory viral load testing or adherence evaluation. They say that further research is needed to validate the risk score and to look at the financial and health trade-offs between switching people unnecessarily to more expensive second-line regimens or leaving people on failing treatment for longer.

Scoring algorithm

Age less than 30

1 point

BMI > 25

2 points

< 7 months on treatment

3 points

7-12 months on treatment

2 points

First rebound VL 10,000-100,000 copies/ml

4 points

First rebound VL > 100,000m copies/ml

2 points

If scoring 9 points or above: switch immediately

If scoring below 9 points: review adherence & carry out confirmatory viral load 3-6 months later

 

 

 

 

Early antiretroviral therapy linked with bone loss in patients with HIV

July 17, 2017

Current HIV treatment guidelines now recommend initiating antiretroviral treatment (ART) at the time of diagnosis. However, a new study has found that such early ART causes greater bone loss compared with deferring ART.

The study followed 399 participants (195 immediate ART and 204 deferred ART) for an average of 2.2 years. Although the study revealed a negative effect on bone density of immediate ART, the overall benefits of ART for preventing HIV transmission and adverse health outcomes prevail. It will be important to understand the long-term consequences of reductions in bone mineral density associated with ART and whether these reductions continue or stabilise with longer therapy.

“What we found was that starting treatment is also associated with accelerated bone loss of about 2-4%, and the rate of decline then appears to slow after the first 2 years of treatment, compared with HIV positive people who deferred treatment,” said Prof. Jennifer Hoy, lead author of the Journal of Bone and Mineral Researchstudy. “We have no cure for HIV, so antiretroviral treatment is for life. An increased rate of bone loss may become important years later, in the setting of increased risk of fragility fracture.”

 

 

Journal Reference:

  1. Jennifer F Hoy   Immediate Initiation of Antiretroviral Therapy for HIV Infection Accelerates Bone Loss Relative to Deferring Therapy: Findings from the START Bone Mineral Density Substudy, a Randomized TrialJournal of Bone and Mineral Research, 2017

 

 

Penis bacteria linked to HIV acquisition

July 17, 2017, by Emily Newman

Three large clinical trials—involving thousands of men in Africa—have shown that male circumcision reduces risk of HIV acquisition. The protection afforded by circumcision is high, with efficacy estimates ranging between 50% and 60%. Some researchers estimate that circumcision helps prevent HIV infection for the male partner simply because it decreases the surface area of skin potentially exposed to HIV infection during sex. Other researchers have a different theory, and it involves the bacteria found on our skin.

At the Conference at Retroviruses and Opportunistic Infections (CROI) held last month, Lance Price, from George Washington University presented compelling research supporting a theory linking the penile microbiome (the colonies of bacteria found on the penis) to HIV risk.

“It’s likely that the bacteria living on our genitalia can affect our HIV risk. Bacteria, interacting with our immune system, can make us more or less susceptible to HIV,” he explained.

The theory is as follows: Men that are uncircumcised tend to have more colonies of bacteria that produce inflammation. Men who are circumcised are less likely to have these types of anaerobic bacteria colonizing the penis. Inflammation, caused by anaerobic bacteria, causes CD4 T-cells to be recruited to the site of inflammation, which then become vulnerable to HIV infection when the virus is present.

Lance showed research comparing the microbiomes between men enrolled in a male circumcision study in Uganda. The researchers compared the types and abundance of penile bacteria among 77 uncircumcised men and 79 circumcised men at baseline between the two groups, and then a year later (one year after people in the circumcision group were circumcised).

In people who were circumcised, the researchers saw a shift in the types of bacteria present—specifically, a significant decrease in total bacterial load, microbiota diversity and microbiota composition. Specifically, the prevalence and absolute abundance of 12 anaerobic bacteria, including anaerobic bacteria like Prevotella and Porphyromonas,were reduced in circumcised men. Circumcised men also had an increase in normal skin bacteria.

 “It’s pretty intuitive that if you change the environment, the organisms that live there are going to change as well. Here, we removed the foreskin, we decrease anaerobic micro environments, and we make it hard for the anaerobes to live,” said Lance.

Lance then explained a case-controlled study of anaerobic bacteria, cytokines (signaling proteins involved in inflammation), and HIV seroconversion. This study, he explained, aimed to determine if there was any association between the types of penile bacteria present, markers of inflammation, and HIV seroconversion. Samples were taken from participants in the two-year male circumcision study conducted in Uganda. Participants were people who seroconverted during the study, each matched to two controls also enrolled in the study.

There were eight penile anaerobes that were significantly associated with the concentration of the inflammatory marker IL-8 (including Prevotella, Dialister, and Porphyromonas). In addition, the odds of HIV seroconversion increased, by 30% to 60%, in the presence of some of these anaerobes, particularly Prevotella and Dialister.

Lance explained that this state, called “anaerobic dysbiosis,” which causes an increase in HIV susceptibility, is largely resolved in response to circumcision. Other factors, like increased washing, may also affect the presence and type of bacteria, he explained during the question and answer portion of the talk.