Tag Archives: Viral load

HIV treatment breaks lead to drug resistance in the female genital tract

Antiretroviral treatment interruptions of 48 hours or more are associated with the emergence of resistant strains of HIV in the female genital tract, investigators report in the online edition of the Journal of Acquired Immune Deficiency Syndromes.

The study included 102 women in Kenya who started first-line antiretroviral therapy based on a non-nucleoside reverse transcriptase inhibitor (NNRTI). Drug-resistant virus was detected in the genital tract of five women in the twelve months after treatment was started. Treatment interruptions were the most important risk factor for this outcome.

“We found that ART [antiretroviral therapy] adherence was a key determinant of genital tract resistance and that treatment interruptions of whatever cause lead to a substantial increase in the hazard of detecting genotypic resistance to antiretrovirals in female genital tract secretions,” write the authors. “Efforts to prevent treatment interruptions by improving program effectiveness, promoting adherence and timely refills, and avoiding the use of more toxic antiretroviral agents could therefore play an important role in reducing transmitted drug resistance.”

First-line HIV therapy often comprises two nucleoside reverse transcriptase inhibitors (NRTIs) combined with an NNRTI. This treatment can have a powerful and durable anti-HIV effect. However, it requires high levels of adherence. Drug-resistant strains of HIV can emerge with poorer adherence. Older drugs in the NNRTI class, nevirapine (Viramune) and efavirenz (Sustiva or Stocrin), have a low barrier to resistance.

Little is currently known about the emergence of drug-resistant virus in the genital tract of women treated with NNRTI-based therapy. This is an important gap in knowledge as drug-resistant virus is potentially transmissible.

Investigators therefore designed a prospective study involving women who started first-line HIV treatment in Mombasa between 2005 and 2008. During the first twelve months after starting therapy viral load was monitored at three-monthly intervals in both plasma and the genital tract. Samples with viral load above 1000 copies/ml were sent for resistance testing. The investigators conducted analysis to see which factors were associated with the emergence of drug-resistant virus in the genital tract.

Overall, the women had high levels of adherence to their antiretroviral therapy. Assessed by pill count, median adherence was 97%. However, there were 40 treatment interruptions. Their median duration was four days. Median pill-count adherence following treatment interruptions was just 83%.

Drug-resistant virus was detected in the blood of nine women (incidence, 10 per 100 person-years) and in the genital secretions of five individuals (incidence, 5.5 per 100 person-years). All five women with resistant HIV in their genital secretions also had resistant virus in their blood.

The investigators’ first set of analysis showed that a number of factors were associated with genital tract resistance. These included treatment interruptions (p = 0.006), pill-count adherence (p = 0.001) and a higher baseline viral load (p = 0.04).

But only treatment interruptions remained significant after controlling for potentially confounding factors. Interruptions were associated with a more than 14-fold increase in the risk of genital tract resistance (aHR = 14.2; 95% CI, 1.3-158.4; p = 0.03).

“The reasons for treatment interruption in this study included both unavoidable discontinuations due to drug toxicity or systemic illness and avoidable interruptions due to late refills, when it is likely that consecutive doses were missed,” note the investigators. “Despite a comprehensive program of adherence support including pre-ART counseling, directly administered therapy during the first month of treatment, a support group, pill boxes and transportation reimbursements, we were unable to prevent these events.”

Transport problems and pharmacy stock-outs have emerged as major barriers to adherence in resource-limited settings. The investigators are concerned that “such barriers may lead to the development of genital tract resistance due to treatment interruptions, suggesting an increased risk for transmission of drug-resistant virus”.

The Aids Library of Philadelphia FIGHT has a video on YouTube which explore the subject of HIV which is resistant to anti-HIV medications. Further information can be found on their website.

Original Article via NAM and Philadelphia Fight’s YouTube Channel

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Gay partners’ HIV transmission study due to start, despite practical barriers

A large study looking at HIV infections in gay men who are within long-term relationships with HIV-positive partners is about to start in Australia, the International Microbicides Conference in Sydney heard last week.

This Opposites Attract study will look at the risk of HIV acquisition by the HIV-negative parter within different-status relationships and hopes to make an estimate of the comparative risks of HIV transmission from HIV-positive partners who are, and are not, on antiretroviral therapy (ART). Initially starting in Sydney, Melbourne, Brisbane and Adelaide, it is planned that the study will expand to other Australian cities and to Thailand.

Calculations of study size and expected loss to follow-up are being informed by findings from a large study of HIV risk in gay male relationships, the HIM study (Bavinton).

The need for a study of HIV transmission risk and the influence of viral suppression in gay men has existed ever since the Swiss Statement in 2008. This said that within certain parameters people with an undetectable viral load could not sexually transmit HIV, but the authors later emphasised that evidence for this was only strong in studies of vaginal sex. The need for further evidence became stronger when the HPTN 052 study found that treating the HIV-positive partner in heterosexual different-status relationships reduced their chance of transmitting HIV by 96%. Since then both the British HIV Association and the US Department for Health and Human Services have recommended ART for prevention purposes in some patients, but both emphasise that the assumption that this will work for gay men is an extrapolation of the data for heterosexuals, and another study recently found that up to a quarter of gay men with no detectable HIV in their blood may have detectable levels in semen.

A study looking at whether treatment works as prevention is thus badly needed in gay men. While a randomised controlled study of immediate versus delayed treatment like HPTN 052 will be difficult to do in the future, given changes in the criteria of ART initiation, an observational study of risk within different-status relationships could be done. The challenge, however, will be that gay male relationships are less likely to be monogamous, and HIV more likely to be transmitted during casual sex, than in heterosexuals. A study was therefore undertaken of different-status and same-status gay male relationships to assess whether a transmission study would be feasible.

The HIM Study findings

The Health in Men (HIM) study is a cohort of 1427 initially HIV-negative gay men recruited in 2001 to 2004 to look at risk factors for HIV, which has provided useful data on risk behaviours in other studies.

In this study, an analysis was done of data originally collected in 2007. HIM subjects completed annual interviews and were asked whether they were in a primary relationship, how long it had lasted, whether their partner had HIV and, if so, whether the subject knew their viral load. Characteristics of different-status and same-status relationships were collected.

Two-thirds of HIM subjects reported being in a primary relationship of which 8.4% (79 individuals) reported that their partner had HIV. This is roughly the same as the proportion of gay men estimated to have HIV in New South Wales (see Prestage). Another 21% of the subjects, however, reported that they did not know their partner’s HIV status.

Within the 79 different-status partnerships, two-thirds of HIV-negative men knew their partner’s HIV viral load, and 58% said it was undetectable.

In terms of contrast between different-status and same-status relationships, some factors were similar, such as age of the HIM subject and their partner, the length of the relationship (roughly 50% had lasted longer than two years) and whether sex was permitted with people outside the relationship.

The rate of relationship breakup was similar too: each year, 29% of different-status relationships and 26% of same-status relationships broke up. Different-status relationships were less likely to break up if they had been going for more than two years, if the HIM subject was over 44, and if the relationship involved ‘serospositioning’ (i.e. the HIV-negative partner was only ever ‘top’ if they had sex without a condom).

Other things were different, though. HIM subjects in different-status relationships were more likely than other subjects to report having sex outside the relationship, having unprotected sex with casual partners, and having tested for HIV in the last three months, and were 2.5 times more likely to report that they were in an open relationship.

Conversely, they were less likely to report having unprotected sex within the relationship, to have ‘negotiated safety’ agreements about no condomless sex outside the relationship, and to be the receptive partner.

There were eight new HIV infections in the 79 men in different-status relationships during the average 3.9 years of follow-up. HIV incidence among men in different-status relationships was 2.2% a year and 0.7% in same-status relationships (hazard ratio: 3.12). HIV acquisition was three times more likely if the HIM subject had been ‘bottom’ with their partner in unprotected sex, and over 15 times more likely if their partner had ejaculated inside them. HIV transmission was six times more likely to occur within the first year of a relationship than after that point and was 4.7 times more likely if the HIM subject was under 35 than if they were over 44.

Conclusions

Presenter Benjamin Bavinton said that these findings posed challenges for the designers of the forthcoming Opposites Attract study. Firstly, the high break-up rate meant that recruitment had to be ongoing throughout the relationship in order to replace attrition due to break-ups. Secondly, high rates of sex outside the primary relationship meant that phylogenetic testing of all HIV infections was essential to establish which were transmissions from the primary partner (results would not be released to participants). Thirdly, Australian criminal law meant that sexual risk behaviour data could only be collected from HIV-negative participants. Fourthly, because infection was so much more common in the first year of relationships, men in new, tentative and not necessarily committed relationships would have to be recruited. And finally, most of the blood tests would have to be done with the initially HIV-negative partner, including when the relationship might have just broken up or just after they had received the news that they had acquired HIV: retention in these circumstances might be a big problem.

Nonetheless, recruitment is about to start: for would-be subjects and professionals interested in the study, there is more information at www.oppositesattract.net.au.

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HIV Infection Increases Risk Of Brain Shrinkage

Results from a small study indicate that certain regions of the brain become significantly smaller in people with HIV. The findings also show that this reduction in brain size occurs even when the HIV infection is well controlled with antiretroviral therapy.

“What we saw was that HIV does affect the brain, and it shrinks areas of the brain,” said Dr. Beau Ances, an assistant professor of neurology at Washington University at St. Louis and lead author of the study. “These areas were just as small in HIV-positive individuals who were and who were not on [antiretroviral] medications,” he added.

Results from the study also suggest that age and HIV infection independently lead to lower brain volumes.

“In particular, we looked at an area that’s very deep in the brain, called the caudate nucleus. We know that the caudate nucleus, which controls some motor movement and planning, is sometimes affected with HIV. We saw that there was an effect of HIV and that there was an effect of aging, but no interactions between them. It looked like HIV aged the brain by about 15 or 17 years or so,” said Dr. Ances.

According to the study authors, results from this exploratory study suggest that administration of neuro-protective therapy may help prevent brain damage in HIV-positive individuals. Dr. Ances noted that the drugs selegeline (Deprenyl, Carbex), minocycline, and valproic acid (Depakote) are neuro-protective agents that have been tested in people with HIV. Results so far have shown no improvement, but he pointed out that starting treatment earlier, before any significant impairment, may be beneficial.

Dr. Ances also noted that previous studies have shown that antiretroviral drugs differ in their ability to reach and penetrate the brain. “HIV gets into the brain and stays in the brain. Are there ways that we could get more of the antiretrovirals into the brain so that we could knock down the virus?” said Dr. Ances. He added that trials are under way to determine the effects of higher and lower penetrating antiretrovirals on brain structure and function.

However, the authors cautioned that larger studies in people with acute and chronic HIV infection are required to more thoroughly understand the effects of HIV on the brain.

Dr. Ronald Ellis, an associate professor of neuroscience at the University of California, San Diego, who was not involved in the study, added that physical exercise might help maintain brain function. “There is a growing body of evidence in non-HIV infected individuals showing that physical exercise benefits the brain. And for that reason, people with HIV may consider using exercise as a way to preserve their brain structure and function,” he said, though he cautioned that this conclusion was speculation.

Previous studies have shown that HIV infection can affect brain function, resulting in lower cognition (see related AIDS Beacon news). In addition, several factors such as aging, vitamin B12 deficiency, or a stroke can lead to the death of nerve cells in the brain, resulting in brain shrinkage (called atrophy).

According to the study investigators, toxic products made by the virus are thought to cause much of the damage observed in the brain. However, the authors noted that HIV-positive individuals continue to show evidence of brain shrinkage and dysfunction despite the advent of highly active antiretroviral therapy (HAART).

As a result, several aspects of HIV infection may be involved in brain impairment. For example, it is possible that long-term exposure to antiretroviral drugs, such as Sustiva (efavirenz), could have toxic effects on nerve cells in the brain. In addition, as the immune system recovers during antiretroviral therapy, brain cells may experience immune-mediated damage.

In this study, researchers aimed to understand the individual effects of HIV infection, HAART, and age on brain size and function. The authors also investigated whether changes in brain volume can serve as a reliable indicator of structural damage in the brain.

A total of 78 individuals participated in the study. A third were HIV negative, a third were HIV positive but had never been on HAART (HAART naïve), and a third were infected and on HAART.

The researchers recorded several HIV-related parameters for each participant, including time since infection, viral load (amount of virus in the blood), and current and lowest recorded (nadir) CD4 (white blood cell) counts.

The average age of HIV-positive, HAART-naïve individuals was 37 years old. About 92 percent were male, and the average duration of HIV infection was three years.

The average age of HIV-positive individuals on HAART was 40 years old. Nearly 85 percent were male, and the average duration of HIV infection was 10.5 years.

HIV viral load was lower and CD4 counts were higher in individuals taking HAART compared to HAART naïve participants. However, the lowest recorded CD4 counts were lower in participants on HAART, possibly due to a longer average duration of infection.

The authors used magnetic resonance imaging (MRI) to estimate the volume of specific regions of the brain. Participants’ responses to a set of questionnaires were used to assess their cognitive function.

After recording initial measurements, 46 percent of the HAART-naïve participants started HAART and all parameters were recorded again after six months of antiretroviral therapy. This data was used to assess the short-term effect of HAART on the brain.

Results from the study showed that HIV-positive individuals performed worse on neuro-psychological tests, as compared to uninfected individuals. Among the HIV-positive participants, HAART-naïve individuals and those taking HAART performed comparably on the tests.

MRI data also showed that HIV-positive individuals, regardless of their HAART status, showed significant reduction in the volume of three specific brain regions – the amygdala, the corpus callosum, and the caudate.

The amygdala is thought to be important in the processing of emotional reactions. The corpus callosum helps the left and right halves of the brain to communicate with each other, and the caudate is involved in learning and memory.

The researchers found that the caudate volume was affected by both HIV and aging. They estimated that HIV infection was associated with a 6 percent reduction in caudate volume for each decade of infection, while aging was associated with an additional 4 percent reduction per decade.

The authors estimated, using modeling techniques, that the caudate volume likely declines gradually for about 13 years after HIV infection, after which it reaches a steady state. Overall, they concluded that the effects of HIV infection on caudate size are equivalent to those of 17 years of aging.

When HAART was introduced in HAART-naïve individuals, viral loads were significantly reduced and CD4 counts increased after six months of therapy. However, the authors observed no change in caudate volumes.

For the corpus callosum and the amygdala, only HIV, and not aging, had an effect on size. Study participants with HIV had a corpus callosum that was an average of 8 percent smaller than participants without HIV, and an amygdala that was an average of 7 percent smaller.

There was no association between reduction in brain volume and viral load or current or lowest CD4 counts. The researchers noted that this result contradicts those from previous studies, which suggested that brain impairment is associated with low nadir CD4 counts (see related AIDS Beacon news).

For more information, please refer to the study in the Journal of Acquired Immunodeficiency Syndrome (abstract).

Original Article via The AIDS Beacon

Every March, Brain Awareness Week (15 – 19 March) unites the efforts of partner organisations worldwide in a celebration of the brain for people of all agesIt is the global campaign to increase public awareness of the progress and benefits of brain research.

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HIV Criminalisation, Sex, Risk & Viral Load In The Real World.

Here are two positive developments that move forward the debate about sex, risk, undetectable viral load and the criminalisation of HIV non-disclosure.

2011 marked the thirtieth anniversary of the HIV/AIDS pandemic. Much has been achieved in those three decades, most notably advances in treatment that have changed the face of HIV for those who have access to antiretroviral (ARV) medication from a terminal illness to a chronic yet manageable disease.

But of late there’s been other good news to celebrate. Just last month, for example, researchers from the University of Western Ontario announced that clinical trials are about to begin on a new HIV vaccine they’ve developed. And it does seem that, increasingly, more and more experts are becoming convinced that +ve individuals, appropriately treated with an undetectable viral load are much less likely to pass on the virus than people not on treatment. However, as PositiveLite editor Bob Leahy recently pointed out by how much and in what circumstances is still subject to debate.

The latest people to take the view that +ve individuals on treatment with undetectable viral loads are unlikely to infect their sexual partners are the two organizations that write the HIV treatment guidelines for the UK, the British Association for Sexual Health and HIV  and the British HIV Association. They’ve done this via their newly revised guidelines for the use of post-exposure prophylaxis (PEP).

PEP is an emergency measure aimed at preventing HIV infection after the possible exposure of an HIV negative person to the virus. The new UK guidelines are notable for no longer recommending that PEP be provided in a number of situations where the “source partner” is known to be HIV+ and to have an undetectable viral load. These situations include unprotected vaginal intercourse, unprotected insertive anal intercourse and oral sex. But PEP is still recommended following unprotected receptive anal intercourse.

The guidelines are also notable for not recommending PEP in any situation in which the source partner is thought not to belong to a social group in which HIV prevalence is high, such as gay men or people from high-prevalence countries (such as those in sub-Saharan Africa). The guidelines also clarify that, due to the very low risk of infection, PEP is unnecessary following human bites or contact with a discarded needle.

(Unlike the UK and many other countries in the developed world, Canada has no national guidelines for the use of PEP for non-workplace exposure – such as unprotected sex, a condom breaking during sex, needle sharing or sexual assault –  although some provincial guidelines exist. As a result, PEP for non-workplace exposure is rarely promoted in Canada. On the other hand, PEP after workplace exposures – for example a health care worker who accidentally suffers a needle-stick injury – remains the “standard of care” and is widely used in this country.)

Yet, despite the growing body of evidence that having an undetectable viral load significantly reduces the likelihood of an infected person passing on the virus to an uninfected sexual partner, Canada has witnessed an escalation in the number of people prosecuted for allegedly exposing partners to HIV even if they had an undetectable viral load and/or were using protection such as condoms or engaging in a low risk activity such as oral sex.  Ontario is home to the majority of HIV-related prosecutions in Canada and is also one of the leading jurisdictions in the world when it comes to such prosecutions.

Part of the problem is that the law around HIV disclosure has never been legally defined. Rather, it comes from a 1998 decision of the Supreme Court that HIV+ people have a legal duty to tell a sex partner that they have HIV before they have sex if there’s a “significant risk” that they’ll pass on the virus to that person. This lack of clarity on what constitutes significant risk has meant that the police, Crown attorneys and lower courts have been inconsistent in how they interpret what sex acts, and under what circumstances, pose a significant risk of HIV transmission.

In last month’s Canadian Medical Association Journal, Julio Montaner, one of Canada’s and the world’s leading HIV medical doctors, along with colleagues from the British Columbia Centre for Excellence in HIV/AIDS called for the end of prosecutions for allegedly exposing sexual partners to the virus. “To put the burden on the person infected with HIV that they have to disclose when they may be on treatment or using a condom, or doing both, is really not appropriate,” Montaner told The Vancouver Sun. “Let me be clear, I think that people who behave irresponsibly, they need to be judged accordingly and there are laws to address those issues…but to have a policy that selectively targets HIV is discriminatory and discourages people from seeking out testing and treatment.”

All this will be coming under intense scrutiny next month, when the Supreme Court of Canada is to hear two appeals involving HIV non-disclosure. In both cases, one from Manitoba, the other from Québec, the accused are HIV+ and had consentual sex with their partners without disclosing their HIV status although they used condoms or were on ARV medication that kept the risk of transmission very low. In each case, the accused were acquitted by the provincial Courts of Appeal. However, prosecutors in both cases applied for an appeal before the Supreme Court.

So it was of particular concern that in September 2011, Ontario’s Attorney General indicated his government’s intention to file an application to intervene in the Supreme Court hearing. The government’s intent was to call on the Court to rule that people living with HIV must disclose their status before any sexual activity whatsoever – even in the case where there’s a negligible, effectively zero, risk of HIV transmission – and that not disclosing should be prosecuted as an aggravated sexual assault, which is one of the most serious offences in the Criminal Code.

It was especially troubling that the Ontario Attorney General‘s office took this position at the same time that it was engaged in ongoing discussions regarding the development of prosecutorial guidelines for allegations of HIV non-disclosure.

So it was good news to learn that, just before Christmas 2011, Ontario quietly withdrew its application to intervene before the Supreme Court. The government hasn’t released its reasons for this about-face, although it must be said that the governing Liberal party has just recently been returned to power following a provincial election where they gained a plurality of seats in the provincial parliament. The premier also appointed a new Attorney General who may have been instrumental in deciding against his predecessor’s decision to intervene.

However, the appeal before the Supreme Court will still be going ahead – it starts on February 8, 2012 – at which time the Court will be asked to define “significant risk”. Hopefully, in reaching a decision on the two cases before it, the bench will take into account current medical and scientific research about the risk of transmission and make a decision that’s compatible with scientific, medical, public health and community efforts to prevent the spread of HIV and to provide care, treatment and support for people living with HIV.

You can listen to an excellent debate about the current law – and recommended changes to it – in a podcast of the CBC Radio current affairs program The Current that was broadcast on December 21, 2011. In it Anna Maria Tremonti talks with Tim McCaskell, a long-time AIDS activist and person living with HIV, and Carissima Mathen, an associate professor of law at the University of Ottawa.

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