This article by Sean Hosein first appeared on the CATIE website here  

Une version française est disponible ici. 

In high-income countries such as Canada, Australia and the U.S. and in regions such as Western Europe, huge advances have been made in the treatment of HIV disease. Researchers increasingly expect that a young person who is diagnosed today and who initiates potent combination anti-HIV therapy (commonly called ART or HAART) and who has minimal co-existing health conditions should have several additional decades of life expectancy.

The combinations of therapies available for the initial treatment of HIV are plentiful. Furthermore, pill taking has been simplified by the availability of the co-formulation of several drugs into one pill, creating an entire regimen in a single tablet. Such single-tablet regimens need only be taken once daily. However, things were not always this way.

A look at the past

Initial treatment for HIV infection, when it became available in the late 1980s, consisted of a single drug—the nuke (nucleoside reverse transcriptase inhibitor) AZT (zidovudine, Retrovir)—given at high doses and taken every four hours. Such a regimen frequently caused headache, nausea, vomiting and damaged the bone marrow.

In the early 1990s, other anti-HIV drugs in the same class became available, including the following nukes:

• ddC (zalcitabine, Hivid)
• ddI (didanosine, Videx)
• d4T (stavudine, Zerit) 

These three drugs, commonly called d-drugs, initially appeared to be better tolerated but soon showed their own side effects, such as peripheral neuropathy (painful nerves in the hands, feet and legs). ddC is no longer manufactured and treatment guidelines in high-income countries now discourage the use of d4T and ddI.

In 1996, a new class of anti-HIV drugs became available—protease inhibitors (PIs). When used in combination with nukes, the results were dramatic. For the first time in the history of the AIDS pandemic, people showed sustained recovery from AIDS-related infections.

However, shortly after HAART became available, reports emerged of a strange syndrome of changes in body shape sometimes associated with the loss of the fatty layer just under the skin. This loss of fat, called lipoatrophy, affected all parts of the body but its effect on the face could become most distressing.

Initially, because PIs were the latest class of anti-HIV therapy, they were suspected as the culprits. However, a few years later, researchers began to realize that exposure to d4T and, to a lesser extent, AZT, was linked to lipoatrophy. Today, drugs such as d4T and AZT are generally not recommended as first-line therapy in high-income countries.

Nukes today

In the current era, nukes remain the backbone of many regimens. Nukes commonly used today include the following combinations:

• abacavir + 3TC – sold as a fixed-dose formulation called Kivexa (or Epzicom) and also found in Trizivir
• tenofovir + FTC – sold as a fixed-dose formulation called Truvada and also found in other combinations such as Atripla, Complera and Stribild 

A lingering sense of caution

Decisions about starting therapy for HIV infection have always been challenging; both doctors and their patients have weighed the risks and benefits, as well as a person’s ability to take HIV medicines exactly as directed for many years. In the current era, with safer, simpler therapies and more results from clinical trials, the risk–benefit ratio has swung strongly in favour of very early initiation of therapy. The most recent version of the U.S. Department of Health and Human Services’ (DHHS) HIV/AIDS Treatment Guidelines recommends early therapy for all HIV-positive people, for two reasons, as follows:

• At the level of the individual, early treatment can help preserve the immune system and improve health.
• From a public health point of view, treating more HIV-positive people reduces the amount of HIV in their blood, other tissues, and genital fluids. The result is decreased sexual infectiousness. As a result of this reduced infectiousness, at the level of a large urban area or region, widespread use of ART can help to reduce new cases of HIV transmission. This approach of treating people to reduce their infectiousness is called TasP—treatment as prevention. 

Despite the general tolerability and safety of Kivexa and Truvada, some HIV-positive people and their doctors remain somewhat wary of nukes in general, given their checkered history, and wonder about the potential of these drugs for causing new, unknown side effects. This latter concern is increased as HIV-positive people age and need to take multiple medications, heightening the potential for drug interactions and side effects.

Emerging research suggests the possibility that nukes can affect the energy-producing parts of cells (mitochondria). However, nuke combinations commonly used in the initiation of therapy today have not been proven to cause mitochondrial damage that is directly linked to the ill health of ART users.

Aging and HIV

Some researchers have found hints of apparently accelerated aging in some HIV-positive people. Specifically, some organ-systems, such as the brain, heart, blood vessels and bones, appear to have aged more quickly than they should.

The cause of this apparent aging is not clear.

If premature or accelerated aging does exist in HIV infection, there may be several potential causes affecting different people, including the following:

• long-term exposure to specific proteins produced by HIV-infected cells
• higher-than-normal levels of inflammation, which accompanies chronic viral infections such as HIV
• substance use
• tobacco smoking
• co-infection with other germs, such as members of the herpes virus family—CMV (cytomegalovirus) and EBV (Epstein-Barr virus) 

The immune system and aging

Several research teams have found that, if left untreated, HIV infection does prematurely age the immune system. HIV appears to cause this by repeatedly activating the immune system and producing inflammation. This virus also appears to cause complex and poorly understood changes to the immune system shortly after it enters the body.

ART greatly reduces HIV-related inflammation but cannot entirely eliminate it. Prolonged exposure to higher-than-normal levels of inflammation is associated with many chronic illnesses and it is possible that such inflammation over the long-term may play a role in reports of accelerated aging seen in some HIV-positive people in studies. However, it is important to bear in mind that exposure to unhealthy behaviours—particularly tobacco smoking—also causes inflammation. Separating all the possible drivers of accelerated aging in HIV-positive people will not be easy and will require many studies, some of them quite expensive and daunting in their complexity.

Much caution needed

A research team in Australia has been exploring the theory that nukes somehow contribute to the apparent acceleration in aging in HIV-positive people. Their work, conducted in complex laboratory experiments on cells from HIV-negative and HIV-positive people suggests the possibility that the drug tenofovir (Viread) may accelerate the aging of the immune system. However, we urge our readers to treat this finding with a great deal of caution, if only because the results from the Australian experiments are not definitive. Furthermore, due to built-in limitations of their study’s design (it is cross-sectional in nature), questions remain about the significance of their findings. Next up, we will explore some of the issues related to the Australian study.

—Sean R. Hosein

REFERENCES:

 1. Boasso A, Royle CM, Doumazos S, et al. Overactivation of plasmacytoid dendritic cells inhibits antiviral T-cell responses: a model for HIV immunopathogenesis. Blood. 2011 Nov 10;118(19):5152-62.

 2. Herbeuval JP, Nilsson J, Boasso A, et al. HAART reduces death ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infected macaques. AIDS. 2009 Jan 2;23(1):35-40.

 3. Bestilny LJ, Gill MJ, Mody CH, et al. Accelerated replicative senescence of the peripheral immune system induced by HIV infection. AIDS. 2000 May 5;14(7):771-80.

 4. Leeansyah E, Cameron PU, Solomon A, et al. Inhibition of telomerase activity by HIV Nucleos(t)ide Reverse Transcriptase Inhibitors: a potential factor contributing to HIV-associated accelerated ageing. Journal of Infectious Diseases. 2013; in press.

 5. Payne BA, Wilson IJ, Hateley CA, et al. Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations. Nature Genetics. 2011 Jun 26;43(8):806-10.

 6. Helleberg M, Afzal S, Kronborg G, et al. Mortality Attributable to Smoking Among HIV-1-Infected Individuals: A Nationwide, Population-Based Cohort Study. Clinical Infectious Diseases. 2013; in press.

 7. Rasmussen LD, Kessel L, Molander LD, et al. Risk of cataract surgery in HIV-infected individuals: a Danish nationwide population-based cohort study. Clinical Infectious Diseases. 2011 Dec;53(11):1156-63.

 8. Guaraldi G, Orlando G, Zona S, et al. Premature age-related comorbidities among HIV-infected persons compared with the general population. Clinical Infectious Diseases. 2011 Dec;53(11):1120-6.

 9. Pathai S, Lawn SD, Weiss HA, et al. Increased ocular lens density in HIV-infected individuals with low nadir CD4 counts in South Africa: evidence of accelerated aging. Journal of Acquired Immune Deficiency Syndromes. 2013; in press.

 10. Smith RL, de Boer R, Brul S, et al. Premature and accelerated aging: HIV or HAART? Frontiers in Genetics. 2012;3:328.

 11. Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS. 1998 May 7;12(7):F51-8.

 12. van der Valk M, Gisolf EH, et al. Increased risk of lipodystrophy when nucleoside analogue reverse transcriptase inhibitors are included with protease inhibitors in the treatment of HIV-1 infection. AIDS. 2001 May 4;15(7):847-55.

 13. Cohen S, Janicki-Deverts D, Turner RB, et al. Association between telomere length and experimentally induced upper respiratory viral infection in healthy adults. JAMA. 2013 Feb 20;309(7):699-705.

This article by CATIE’s James Wilton and Logan Broeckaert first appeared on the CATIE  website here.

Une version française est disponible ici.

We have known for years that antiretroviral therapy can significantly improve the health outcomes of people living with HIV. More recently, research has revealed the important role that antiretroviral therapy plays in preventing the transmission of the virus. As HIV treatment and prevention have converged, attention has turned to how well we are engaging people living with HIV in the continuum of services, including testing, care and, ultimately, effective treatment. The concept of an HIV treatment cascade has emerged as a way to identify gaps in the continuum, which are preventing people from realizing the treatment and prevention benefits of antiretroviral therapy.

This article takes a closer look at the cascade, why it’s important for HIV prevention and how it can be improved.

Steps in the HIV treatment cascade

Antiretroviral therapy is normally considered successful when it reduces the viral load of a person living with HIV to undetectable levels. Research shows that people who have an undetectable viral load in their blood are more likely to live a long and healthy life1 and are less likely to pass HIV to others.2

For a person living with HIV to achieve an undetectable viral load, they need access to a continuum of services: HIV testing and diagnosis, linkage to appropriate medical care (and other health services), support while in care, access to antiretroviral treatment if and when they are ready, and support while on treatment. This sequence of steps is commonly referred to as the HIV treatment cascade or the HIV care cascade. Unfortunately, the cascade isn’t seamless and some people “leak” out and are lost at each step, due to barriers to getting tested, staying in care, and starting or adhering to antiretroviral treatment. These barriers include:

• poor access to services;
• stigma and discrimination;
• poverty, food insecurity and homelessness; and
• mental health and addiction issues.3

As a result of these leaks at different points in the continuum, only a small proportion of people living with HIV are engaged in all the steps needed to achieve an undetectable viral load. For example, in the United States it is estimated that only 19% to 28% of people living with HIV have an undetectable viral load (see Figure 1).4,5

Figure 1. Engagement in the HIV treatment cascade in the United States

Source: Adapted from the Centers for Disease Control and Prevention – Morbidity and Mortality Weekly Report, December 2nd, 2011.

There are currently no official estimates for the number of people engaged in the treatment cascade in Canada; however, preliminary data suggest that there are also significant leaks in the cascade in Canada and that the proportion of people with an undetectable viral load may be similar to that in the United States6 (although it likely varies across regions and for different populations).

Patching the cascade to improve treatment and prevention

Poor engagement of people living with HIV with healthcare and social services limits the effectiveness of our HIV programs and our response to the HIV epidemic. Increasing the number of people engaged at all levels of treatment and care may both improve the health of people living with HIV and reduce new HIV transmissions. Increasing engagement in the cascade requires programs that address the multiple barriers.

However, we do not know what the “ideal” cascade should look like and aiming to get everyone living with HIV on successful treatment is not realistic, nor would it be ethical. It’s critical that efforts to better engage people in services do not come at the cost of individual rights and that we make sure clients and patients are ready and willing to take each step. To ensure informed consent, the risks and challenges that come with testing positive for HIV and starting treatment need to be explained to clients and patients before they make these important decisions.

Let’s take a look at each step of the cascade, its importance for treatment and prevention, and how we might be able to better engage people in each step.

HIV testing and diagnosis

An estimated 26% of people living with HIV in Canada do not know they have HIV.7 Reducing the number of people who are unaware of their HIV status requires increased uptake and frequency of HIV testing.

Increasing the frequency and rates of HIV testing will help diagnose people sooner after they have become infected with HIV. Currently, many people in Canada are not learning about their HIV status until late in their HIV disease, when they start to develop symptoms or opportunistic infections.8 At this point, antiretroviral treatment can help improve their health, but not as effectively as when treatment is started earlier.9,10 Furthermore, research suggests that a disproportionate number of HIV transmissions originate from people who are unaware of their HIV status because they are less likely to take measures to prevent transmitting the virus to others 11 and are more likely to have a higher viral load, particularly if they have recently become infected and are in the acute stage of HIV infection.12 Earlier diagnosis is therefore important for both the health of a person living with HIV and for preventing the transmission of the virus.

These are some of the interventions being used in Canada to promote HIV testing and diagnose people earlier:

Campaigns to improve awareness of HIV risk and encourage people to get tested regularly. Campaigns such as Get on it in Ontario, Find out where you stand in Montreal, and What’s your number? and Hottest at the Start in Vancouver encourage gay men and other men who have sex with men to test regularly for HIV. Some of these also aim to improve awareness of acute HIV infection and its role in HIV transmission.

Improving access to more acceptable types of HIV testing, such as point-of-care (POC) antibody testing and peer testing, to increase options for people who want to get tested. For example, POC testing is now more widely available in large Canadian cities. Peer outreach and testing in gay bathhouses is offered by some organizations, such as Toronto’s Hassle Free Clinic. In Montreal, the SPOT Project offers gay men anonymous HIV rapid testing and counselling as well as a full range of tests for sexually transmitted infections (STIs) from a storefront site.

Improving access to tests that have shorter window periods and can detect HIV infection earlier than antibody tests. These tests can help identify people in the acute stage of HIV infection. For example, P24 antigen testing has been used in Ontario since 2010 and a pilot study using nucleic acid amplification (NAAT) testing is currently underway in Vancouver.

Making HIV testing a routine part of healthcare to increase the number of people offered an HIV test. For example, Vancouver is scaling up HIV testing; primary care facilities, acute care hospitals and a few dental clinics in the city are now routinely offering HIV tests to patients.

Integrating HIV testing with testing for other STIs. Some organizations, such as the Hassle Free Clinic, offer an HIV test to anyone seeking STI testing. This greatly increases opportunities for HIV testing since people are more likely to seek testing and treatment for other STIs than for HIV.

Enhanced partner notification services to better identify and diagnose people who may have been exposed to HIV. Some regions, such as Vancouver, are re-examining how they perform partner notification to improve the effectiveness of the service.

Linkage to care and support

Linking people who receive a positive diagnosis to accessible and culturally appropriate care and support services is important to ensure that people living with HIV enter the next step of the treatment cascade. Research shows that delays in linkage to medical care after HIV diagnosis are associated with faster disease progression.4 Interventions that currently improve linkage to care in Canada include the following:

Referral systems that link people diagnosed with HIV into care. For example, the Manitoba HIV program, which provides a wide range of integrated care and support services at two sites in Winnipeg, has a referral line for people who test positive. This line can be used by the healthcare provider who performed the test to refer newly diagnosed individuals to the Manitoba HIV program for care.

Improved outreach interventions. For example, the STOP Outreach Team in Vancouver uses case-management to connect people with complex needs to the most appropriate service or program and ensures strong engagement in care before discharging them from the team’s caseload.

Retention in care and adherence support

Once linked to care, a person needs to be supported and monitored and receive counselling to determine when they are ready and eligible to start treatment. Once a person decides to start treatment, remaining in care is important so a person can be supported with adherence and receive ongoing viral load monitoring to ensure that their treatment is working.

Appropriate care and support for people living with HIV may include a wide range of services in addition to medical care, such as mental health and addiction services, adherence support, affordable housing and prevention counselling. These services can improve the quality of life of people living with HIV, address the underlying reasons people may drop out of care or find it difficult to adhere to treatment, and improve sexual well-being. Research shows that a combination of medical care and additional types of care and support improve the health outcomes of people living with HIV13 and make them less likely to engage in behaviours that can lead to HIV transmission.14

Recently, the International Association of Providers of AIDS Care released guidelines for healthcare providers that contain 37 evidence-based recommendations to improve retention in care and adherence to antiretrovirals.

• Interventions and services are offered across Canada that keep people engaged in care and help them access treatment, adhere to their medications and prevent the transmission of HIV.
• Intensive case management approaches can improve engagement in care by providing tailored support to individuals who need it. For example, the Manitoba HIV program proactively follows up with people who entered the program but have been lost to care and provides highly individualized services to people who have a history of lapses in care.
• Maximally assisted therapy (MAT) programs deliver daily treatment and support services to their clients. For example, the Positive Outlook Program at Vancouver Native Health Services and the MAT program at the Downtown Community Health Centre in Vancouver both provide assistance with daily treatment adherence and comprehensive support to their clients.
• Peer navigator programs train HIV-positive peers to offer services to people living with HIV who face multiple barriers to engagement. For example, Positive Living BC’s peer navigators provide tailored support to people who need it. They do this through community outreach and at the Immunodeficiency Clinic at St. Paul’s Hospital.  
• Programs that offer psychosocial supports, such as housing and food security programs, can reduce structural barriers to engagement in HIV care and treatment. For example, La Corporation Félix Hubert d’Hérelle in Montreal, the SHARP Foundation in Calgary, and many others across the country offer housing and housing supports to people living with HIV. A Loving Spoonful in Vancouver offers 1,200 meals a week to people living with HIV.
• Programs that support people living with HIV to live healthy sexual lives and incorporate prevention as part of their overall health and well-being. For example, the Poz prevention program at Toronto People With AIDS Foundation provides peer consultations, training for service providers and group discussions on sexual health and HIV prevention.

What can you do?

Public health authorities, healthcare providers and frontline service providers all have a role to play in making services more accessible and providing people with ongoing care. 

Patching the leaks in the cascade may require new interventions and new partnerships and/or the re-conceptualization of how services are integrated and linked with other services. It may also involve changing how services are evaluated. 

Key questions to ask yourself and your organization are:

• How can your organization better engage people living with HIV in the treatment cascade?
• What additional services could your organization provide to improve engagement in one or more steps of the cascade? Can you learn from what other agencies have done? Would it work in your region?
• What initiatives or partnerships could you develop to connect people living with HIV to your services? What initiatives or partnerships could you develop to connect your clients with other relevant services in your community?
• How can you evaluate whether your clients are entering the next step of the cascade? 

As we work to improve engagement in the treatment cascade, it is critical that human rights are respected and that people living with HIV and at risk of HIV are empowered through information to make decisions about testing and treatment that are right for them. This includes information about the legal requirement to disclose prior to some sexual activities.

Improving HIV treatment and prevention

Each step in the cascade is important for improving the health of people living with HIV and preventing new transmissions. The idea of a treatment cascade is useful for conceptualizing how services are linked and for identifying gaps that need to be addressed. At the same time, it has several shortcomings. First, it represents care for people living with HIV as a linear process, which we know isn’t always the case. For example, a person living with HIV may fall out of care or stop treatment for various reasons, they may move backwards or forwards at different points along this continuum, or they may receive healthcare for many years without starting treatment. When developing programs and services, we need to take these realities into account. Secondly, the concept of a treatment cascade does not include prevention as a component of an effective response. As a model of care for people living with HIV, it indirectly reinforces the false view that the responsibility for HIV prevention rests solely with people living with HIV. In fact, prevention is a shared responsibility and all people, regardless of serostatus, have an important role to play. Additionally, treatment as a mechanism for prevention is only one of several effective prevention strategies, all of which, when appropriately combined will provide a more effective response to the HIV epidemic than any one strategy alone. We should no longer do prevention work in isolation of those working in HIV testing, treatment, care and support, as they are all reinforcing elements of an effective response to HIV.

While each organization has a role to play in improving care for people living with HIV, we also need to look at the issue from a systemic level. How can we, as policymakers, service providers, healthcare providers and people living with HIV, improve services for people living with and at risk of HIV? We need to identify gaps and ways to improve care in conjunction with the community, to ensure that a person can effectively navigate their way within the healthcare system. Fragmented, stand-alone programs and services need to be linked to ensure that people living with and at risk for HIV have access to services that can support their care. 

In September 2013, CATIE will host a national forum called New Science, New Directions in HIV and Hepatitis C. This forum will provide an opportunity for frontline workers to come together to learn about new directions in service provision, share programming experiences and strategize about developing more integrated approaches to treatment and prevention.

Resources 

TreatmentUpdate – HTPN 052: The trial that changed everything

Prevention in Focus – Detecting HIV earlier: Advances in HIV testing

Prevention in Focus – Recently infected individuals: A priority for HIV prevention

Prevention in Focus – The STOP HIV/AIDS Project: Treatment as prevention in the real world

References

1. Nakagawa F, Lodwick RK, Smith CJ et al. Projected life expectancy of people with HIV according to timing of diagnosis. AIDS. 2012 Jan;26(3):335–43.

2. Cohen MS, Chen YQ, McCauley M et al. Prevention of HIV-1 infection with early antiretroviral therapy. New England Journal of Medicine. 2011 Aug 11;365(6):493–505.

3. Hull MW, Wu Z, Montaner JSG. Optimizing the engagement of care cascade. Current Opinion in HIV and AIDS. 2012 Nov;7(6):579–86.

4.a. b. Gardner EM, McLees MP, Steiner JF et al. The spectrum of engagement in HIV care and its relevance to test-and-treat strategies for prevention of HIV infection. Clinical Infectious Diseases. 2011 Mar 1;52(6):793–800.

5. Vital signs: HIV prevention through care and treatment--United States. MMWR Morb. Mortal. Wkly. Rep. 2011 Dec 2;60(47):1618–23.

6. Adam BD. Epistemic fault lines in biomedical and social approaches to HIV prevention. Journal of the International AIDS Society. 2011;14(Suppl 2):S2.

7. Government of Canada Public Health Agency of Canada. HIV/AIDS Epi Updates—July 2010. [Internet]. Available from: www.phac-aspc.gc.ca/aids-sida/publication/epi/2010/2-eng.php

8. Althoff KN, Gange SJ, Klein MB et al. Late presentation for human immunodeficiency virus care in the United States and Canada. Clinical Infectious Diseases. 2010 Jun;50(11):1512–20.

9. Li X, Margolick JB, Jamieson BD, Rinaldo CR et al. CD4+ T-cell counts and plasma HIV-1 RNA levels beyond 5 years of highly active antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes. 2011 Aug 15;57(5):421–8.

10. Siegfried N, Uthman OA, Rutherford GW. Optimal time for initiation of antiretroviral therapy in asymptomatic, HIV-infected, treatment-naive adults. Cochrane Database of Systematic Reviews. 2010 Mar 17;(3):CD008272.

11. Marks G, Crepaz N, Senterfitt JW, Janssen RS. Meta-analysis of high-risk sexual behavior in persons aware and unaware they are infected with HIV in the United States: implications for HIV prevention programs. Journal of Acquired Immune Deficiency Syndromes. 2005 Aug 1;39(4):446–53.

12. Miller WC, Rosenberg NE, Rutstein SE, Powers KA. Role of acute and early HIV infection in the sexual transmission of HIV. Current Opinion in HIV and AIDS. 2010 Jul;5(4):277–82.

13. Giordano TP, Gifford AL, White AC et al. Retention in care: a challenge to survival with HIV infection. Clinical Infectious Diseases. 2007 Jun 1;44(11):1493–9.

14. Metsch LR, Pereyra M, Messinger S et al. HIV transmission risk behaviors among HIV-infected persons who are successfully linked to care. Clinical Infectious Diseases. 2008 Aug 15;47(4):577–84.

About the author(s)

James Wilton is the coordinator of the Biomedical Science of HIV Prevention Project at CATIE. James is currently completing his master’s degree of Public Health in Epidemiology at the University of Toronto and has completed an undergraduate degree in microbiology and immunology at the University of British Columbia.

Logan Broeckaert holds a Master’s degree in History and is currently a researcher/writer at CATIE. Before joining CATIE, Logan worked on provincial and national research and knowledge exchange projects for the Canadian AIDS Society and the Ontario Public Health Association.

Testing has become one of the most prominent of HIV messages. Its centrality to HIV prevention is strengthened by all the benefits of treatment, and the earlier the better. 

To reduce current levels of late and very late diagnosis currently recorded, early recognition and detection are essential. 

The rationale for promotion of testing cannot be flawed. Testing for HIV is integral to tackling HIV at both population and at individual levels. A key question, however, touches upon balance in our messages and on where HIV testing fits in an overall strategy and its effect on prevention. 

Strategies 

Most HIV strategies include about seven actions on testing, such as:

1. Tailoring the HIV test to individual risk
2. Extension of testing to primary care and other non-HIV specialist settings
3.  Normalising attitudes to testing in public and professionals_
4. Testing routinely in cases of indicator illnesses
5. Combining HIV testing with testing for syphilis and viral hepatitis
6. Staff training on HIV and testing
7. Addressing the problem of HIV and related stigma

In particular, primary and non-specialist care settings, routine indicator tests, and staff training have potential for quick and significant benefits. 

Individuals of course are often ahead of planners and providers. People are fairly savvy when it comes to working out ways of reducing risk. Three decades of safer sex knowledge within communities must have made an impact. For example, long after positive people had twigged the impact of treatment on infectivity, the ‘Swiss Statement’ broke this knowledge. What the scientists and clinicians added to existing knowledge were the important caveats such as ‘no concurrent STI’. 

‘Sero-sorting’ trickled equally slowly into health promotion literature, eventually being adopted as a component of a form of ‘harm reduction’ beyond safer sex. In addition to negotiation, openness and honesty in a relationship, knowing one’s status is an essential part of this individual protective strategy. 

HIV testing needs to be carefully calibrated to the perceptions, needs, fears and hopes of those targeted. To get the most out of our testing and health promotion strategies, must to listen to intelligence ‘on the ground’. Research in this area is crucial, though it comes also from hearing and sharing the experience of clinics and outreach teams. 

The purpose of HIV testing 

The primary purpose of HIV testing is the health of the individual, and cannot be an end in itself. Too many people encounter several stages in the health system before being diagnosed, resulting in very costly late diagnosis. One of the disadvantages of testing tailored to individual risk lies in equating risk with identity. Some people would never contemplate taking an HIV test. They may have to be nudged in the right direction provided it’s based on good current information and avoids stereotyping. If this were supported by a broad-based information campaign, then we might net some of those who are testing late. 

Testing’s primary purpose of getting people well is consistent with its impact on prevention to which it is integral. Indeed laboratory testing costs, for example, are often covered by prevention budgets. Along with health promotion, testing is fundamental to prevention. That the diagnosis of HIV is also a public health strategy need not detract from benefit to the individual. Treatment as prevention, that is early treatment to reduce viral load and therefore infectivity, demonstrates the overlap between individual and public health. 

Are we placing too much store by HIV testing? Even where testing rates have improved significantly, this advance is not reflected necessarily in a drop in either prevalence or incidence. Even high levels of treatment and viral suppression have not yielded the public health results we might expect. Percentages of positive people on treatment and virally suppressed need to be very high to drive down prevalence and incidence at populations levels. 

Other contributory factors include rising rates of unprotected sex, and of course undiagnosed infection. Once the percentage of those positive people who are either undiagnosed or not on treatment are subtracted, then even creditable universal health systems struggle to push above the 60% mark of undetectable. 

In this respect, nad using an Australian example,  the goal in New South Wales is to have 90% of people with HIV undetectable by 2015, an ambitious target  Is this achievable, given real life? 

What must we do? 

Where testing strategies often get bogged down is in a lack of equity with uneven national coverage and lack of intensification. 

While approaches targeted on those most at risk make sense, we also have to think beyond the obvious. There are far too many lost opportunities as doctors miss indicator conditions or think only in terms of stereotype. 

Once testing strategies are in place, it’s time for action. The connection, however, cannot be assumed. Word-perfect outreach, protocols, referral and testing campaigns are no guarantee of getting people through the door. Unfortunately, lack of monitoring and accountability allow this to go unremarked. 

The most successful advances in HIV testing have been based on practical approaches such opt-out and no-talk testing, and partner notification have been driven by clinics. Now what we need is the careful extension of testing to new settings such as primary care or emergency units. It is a matter of urgency for these to be promoted and resourced. In higher prevalence areas, a number of GP practices may have developed clinical experience and credibility with patients, which can be shared with other GPs. 

Community testing approaches work well. Careful planning, good collaboration between clinic and community, and drawing on their respective skills and competences ensure rapid referral and care. 

A plea from various quarters for more psychological support throughout HIV work still has to be heard. Full clinical psychology in every HIV unit is too much to expect, but this level of one to one intervention is recognised as a means of engaging in-depth with those at risk, who don’t test, or who repeat test. 

To be continued . . . 

This article by Gus Cairns first appeared on aidsmap.com here.  

A paper in The Lancet Infectious Diseases by scientists from the UK’s Medical Research Council and the Health Protection Agency (HPA) has calculated that the number of gay men in England and Wales who become infected with HIV each year remained unchanged between 2001 and 2010. This is despite a considerable increase in testing and, they estimate, a 40% reduction in the proportion of gay men with HIV who are undiagnosed.

The paper concludes that, in England and Wales at least, the proportion of gay men with HIV who are on treatment and with undetectable viral loads is currently too low to bring about a decline in annual HIV incidence in this population. This is in contrast to declines in diagnosis, and claims of declines in incidence, seen in places such as San Francisco, the province of British Columbia in Canada, and some locales in South Africa.   

As well as extending HIV testing to non-traditional settings and urging gay men to test more frequently, the authors conclude that “the initiation of treatment on diagnosis, regardless of CD4 count might well be necessary to achieve control of HIV transmission”, and welcome the new BHIVA treatment guidelines' recommendation "that clinicians discuss the benefits of early treatment uptake as a prophylaxis to protect sexual partners” as a step towards this.

Calculating incidence

The paper is a mathematical model. It uses available data on diagnoses, CD4 counts at diagnosis, and the proportion of people on antiretroviral therapy (ART) to make estimates of the true annual number of infections (annual incidence) in gay men, the number undiagnosed, average time gap between infection and diagnosis, the distribution of CD4 counts among diagnosed and undiagnosed men and the proportion who are on treatment and with an undetectable viral load.

Although mathematical models are always estimates, in this case surveillance data from the UK are of good enough quality to make them quite robust, though because by definition fewer very recent infections are diagnosed, incidence estimates for the last two years are less certain than for previous years.

The incidence rate is not the same as the new diagnosis rate in HIV, because of the time lag between infection and diagnosis. If the number or frequency of HIV tests go up, the number of diagnoses will tend to go up, since more long-term undiagnosed infections will be identified. The researchers got round this problem by using CD4 count at diagnosis – available for the majority of diagnosed people in England and Wales – as a surrogate for the time delay between infection and diagnosis, given that CD4 counts in people with untreated HIV tend to decline at an even rate over time.  

Results – diagnosed and undiagnosed

The number of diagnoses in gay men in England and Wales increased from about 1800 in 2001 to 2600 in 2010. However by adjusting this for CD4 count at diagnosis, the researchers estimated that the true annual total of HIV infections in gay men had remained virtually unchanged, from 2200 in 2001 to about 2300 in 2010. There was an increase in incidence to about 2700 a year in 2003-4, due to increased rates of sex without condoms in gay men, but this has reduced since.

This reduction is due, the researchers say, to more gay men taking tests and to a shorter period between HIV infection and diagnosis. The number of HIV tests taken by gay men in sexual health clinics has grown nearly fourfold, from 16,000 in 2001 to 59,300 in 2010. As a result, the estimated time between infection and diagnosis has shrunk from four years to 3.2 years during this time, and the proportion of gay men with HIV who are undiagnosed from 37 to 22%.

The reason it has not shrunk more, say the authors, is due to gay men not testing often enough. Last year, study co-author Valerie Delpech of the HPA told the IAPAC Prevention Summit that only an estimated 10 to 15% of gay men took an HIV test every year, and that two-thirds of gay men who had had a test at a clinic had, two years later, not returned to that clinic for another one.  

Because there are (as of 2010) 3.2 years’ worth of undiagnosed infections in the population, the total number of gay men with HIV who are undiagnosed in England and Wales was estimated as 7690 in 2010. This was only a small increase from 7370 in 2001 and represents a 16% decline from 9140 in 2004-5, again due to more testing.

The proportion of gay men with HIV who are undiagnosed has gone down by 40% while the number has scarcely changed because total HIV prevalence and the number of UK gay men living with HIV has grown over the same period.

Results – implications for treatment

In 2001, at HIV diagnosis, about 65% of gay men had a CD4 count under 500 cells/mm3, 40% under 350 cells/mm3, and 18% under 200 cells/mm3. Ten years later, the proportion in these three categories had only fallen by about 5%. This means that less than 40% of gay men would currently be advised, under treatment guidelines, to begin taking antiretroviral therapy (ART) for treatment reasons as soon as they are diagnosed.

The researchers calculated that, because more undiagnosed infections are recent ones, only 20% of undiagnosed gay men had a CD4 count under 350 cells/mm3 and only 45% under 500 cells/mm3. Further decreasing the proportion of gay men with HIV who are undiagnosed, and raising or abolishing the CD4 threshold for treatment initiation, would therefore have considerable cost implications for the National Health Service in England and Wales.

Conclusions

In many ways, the UK’s response to HIV has been excellent. The proportion of gay men with a CD4 count under 350 cells/mm3 who are on ART has increased from 75% in 2001 to 84% in 2010; 65% of all patients in care, including the untreated, have undetectable viral loads; and annual loss to follow-up of those attending care is under 5%.

In the US, in contrast, it is estimated that there are more gay men who are diagnosed but not taking ART than there are undiagnosed, and that only 28% of people with HIV are virally suppressed. But gay men in other countries test more frequently: as an accompanying editorial by Reuben Granich of UNAIDS points out, the 22% of gay men who remain undiagnosed in the UK is not as good as an estimated 14% in Vancouver and only 6% in San Francisco.

Because most of those with detectable viral loads in the UK are undiagnosed, it is estimated by the HPA that up to 50% of HIV infections in gay men here could be being transmitted by men in primary HIV infection and another 35% by undiagnosed men with long-term infection. The authors conclude that treatment initiation at diagnosis, earlier, more targeted testing, and better primary HIV prevention all need to be part of any national HIV prevention plan for England and Wales.

References

Birrell PJ et al. HIV incidence in men who have sex with men in England and Wales 2001-2010: a nationwide population study. The Lancet Infectious Diseases, early online edition: http://dx.doi.org/10.1016/S1473-3099(12)70341-9. See abstract here. 2013.

Granich R HIV in MSM in England and Wales: back to the drawing board? The Lancet, early online edition: http://dx.doi.org/10.1016/S1473-3099(13)70035-5. See first few lines here. 2013.

This article by Michael Carter first appeared on aidsmap.com here. 

New Swiss research shows the importance of observing antiretroviral treatment guidelines, even in people who have well-controlled HIV infection. Published in the online edition of the Journal of Acquired Immune Deficiency Syndromes, the study demonstrated that toxicities and concerns about long-term side-effects were common reasons for switching to recommended treatment. CD4 cell count, viral load and adherence either remained stable or improved after the treatment change.

“Our results demonstrate the benefit of observing available cART [combination antiretroviral therapy] recommendations and suggest that recommendations should be observed even in well-controlled patients,” comment the authors.

HIV is a particularly complex area of medicine. There are expert consensus guidelines to enable physicians to prescribe the safest, most appropriate combination of anti-HIV drugs. These are updated regularly to reflect advances in HIV medicine.

Certain combinations of antiretroviral drugs are not recommended because of concerns about their safety and efficacy.

This includes the use of therapy based on double boosted protease inhibitors; treatment consisting of three nucleoside reverse transcriptase inhibitors (triple NRTI); and the combination of d4T (stavudine, Zerit) with ddI (Videx).

A team of investigators looked at the prescribing practices of HIV physicians in Switzerland between 2006 and 2010.

The retrospective study involved participants enrolled in the Swiss HIV Cohort Study who were taking antiretroviral therapy and who had an undetectable viral load.

Three non-recommended regimens in 2006 US guidelines were included in the authors’ analysis: double boosted protease inhibitors (104 participants); triple-NRTI therapy (436 participants); and a combination including d4T/ddI (21 participants). They compared the characteristics of these participants with those of 3171 individuals taking recommended regimens and looked at the factors associated with switching to recommended combinations of drugs and outcomes after changing treatment.

There were a number of significant baseline differences between participants taking non-recommended combinations and individuals prescribed standard HIV therapy.

Individuals prescribed double boosted protease inhibitors had more advanced HIV disease and were highly treatment-experienced. Their adherence was poorer and their cholesterol and triglycerides were higher, even though they were more likely to be prescribed lipid-lowering medication.

Participants in the triple-NRTI group were less likely to have advanced HIV disease and had less experience of antiretroviral treatment.

“The association between recommendation non-adherence and high CD4 count may be due to perceived level of security on the part of the prescribing physician,” suggest the investigators. 

However, participants taking triple-NRTI therapy had a higher Framingham risk score (ten-year risk of cardiovascular disease) than the control patients and most were under the care of private practitioners. The authors explain: “Private practitioners are HIV community physicians who care for less ill patients such as those on triple-NRTIs.”

Individuals prescribed d4T/ddI were more likely to be receiving care at a peripheral hospital and more than half frequently missed doses of their medication.

In September 2007, 73% of participants prescribed a double boosted protease inhibitor at baseline were still taking this regimen. The proportion had fallen to 23% in September 2010. Women and individuals with a higher CD4 cell count were more likely to continue to take this combination. All participants with diabetes or a history of cardiovascular disease switched to an alternative regimen.

Most participants taking a triple-NRTI combination remained on this regimen throughout follow-up (2007 = 86%; 2010 = 53%). Participants with a history of cardiovascular disease were more likely to switch. Those who maintained an undetectable viral load were more likely to remain on the treatment until 2010.

The proportion of participants remaining on the d4T/ddI combination fell to 47% in 2007. By 2010, just one individual was still taking these two drugs.

The most common reason for switching from a double boosted protease inhibitor was the choice of the physician (39%), followed by decision of the participant (17%), concerns about cardiovascular disease (14%) and other toxicities (10%).

Lipodystrophy (29%) was the main reason why participants stopped triple-NRTI treatment. Other common reasons included decision of the doctor (19%) and decision of the patient (11%).

Switching from d4T/ddI was most often due to a decision by the doctor (33%), followed by lipodystrophy (22%), other toxicities (11%) and concerns about cardiovascular disease (11%).

Changing to recommended therapy had benefits for participants. These included a better chance of sustaining an undetectable viral load for individuals who had been prescribed triple-NRTI treatment (p = 0.02) and a trend towards improved adherence for participants switched from d4T/ddI.

The authors suggest that these reasons show that “clinicians observe recommendations when they become ‘relevant’ to patients…clinicians seem to react to an event once it has happened, rather than switch cART as primary prevention, if patients exhibit good virological and immunological control.”

Despite this, they conclude that switching to recommended treatment has benefits for patients.

Reference

Boillat-Blanco N et al. Impact of recommendation updates in well-controlled patients on non-recommended antiretroviral therapies: the Swiss Cohort Study. J Acquir Immune Defic Syndr, online edition. DOI: 10.1097/QAI.0b013e31827b26a, 2012.