Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
Please could you tell us a little bit about the mechanism by which HIV infects people?
Sexual intercourse is the major mode of HIV transmission. HIV may also be transmitted through sharing of needles or contaminated blood products (although this is rare).
It has been shown that the risk of infection during sex, amongst other factors, is greater in individuals with a sexually transmitted infection, such as syphilis, genital herpes, chlamydia, gonorrhea, bacterial vaginosis, or trichomonas. Infants from a mother infected with HIV are at a greater risk of being infected, particularly before or during birth or through breastfeeding.
Once in the body, HIV infects cells in the human immune system such as helper T cells (specifically CD4+ T cells), dendritic cells, and macrophages. HIV virus deplete CD4+ T cells through killing of infected cells (directly or through CD8 cytotoxic lymphocytes) or by increasing rates of apoptosis in infected cells.
When CD4+ T cell numbers decline below a critical level, the immune system becomes fragile, and the body progressively more susceptible to opportunistic infections.
Can you explain us how antiretroviral therapy has been scaled up in low and middle income countries?
To scale up therapy, countries used the public health approach of antiretroviral therapy, which means: the use of simplified and standardized first- and second-line antiretroviral treatment regimens, including fixed-dose combinations; initiation of therapy and monitoring of patients using simple clinical criteria and laboratory tests; making optimal use of limited human resources by shifting routine patient monitoring and follow-up tasks from physicians to nurses and community workers; and extensive involvement of affected communities and people living with HIV/AIDS in programme design and delivery, especially in the areas of community education and patient support.
The public health approach has represented a tremendous advance for treatment scale up, expanded access and promotion of health equity.
How does resistance against HIV drugs develop? What factors play a role?
HIV drug resistance refers to the ability of the virus to withstand the effects of a given antiretroviral drug to prevent its replication.
Resistance is the consequence of the high replication rate of the HIV virus and its inability to correct errors (what we call mutations) that occur during its replication. As a consequence, drug resistant virus continue to replicate in the presence of the drug to which it has become resistant.
Suboptimal exposure to drugs (mainly due to the fact that people do not take their medication correctly or because of interrupted drug supply) favors the emergence and the selection for the mutations that confer resistance to the antiretrovirals (this is what we call “acquired drug resistance”).
People failing therapy and carrying resistance virus can then transmit resistant-HIV to other previously uninfected individuals. This is called “transmitted drug resistance”.
It has recently been reported that drug-resistant HIV has been increasing in parts of Sub-Saharan Africa since to the introduction of antiretroviral therapy (ART) around a decade ago. Could you explain why this is important news? Is it worrisome?
In our paper recently published in The Lancet we investigated whether the prevalence of HIV-1 drug resistance had increased over time in treatment-naive individuals with HIV since initiation of ART roll-out in resource-limited settings.
The findings of our paper are consistent with the data just released by the Word Health Organization in the recent HIV Drug Resistance Report (www.who.int/hiv/pub/drugresistance/report2012), and suggest:
- that levels of resistance, particularly to one class of drugs called NNRTI, have increased is some areas of Africa since ART roll out;
- that higher resistance levels are observed in areas with greater antiretroviral therapy coverage;
- that despite resistance has increased in untreated people, it is still under control, meaning that the majority of people initiating therapy are likely to respond to currently available drugs used for first line therapy and no changes in antiretroviral treatment guidelines are warranted at the moment.
However, as treatment continue to be expanded in resource limited setting, resistance may rise further, and we must be vigilant.
Why is resistance in untreated individuals important?
We were interested to assess resistance in untreated individuals because the detection of resistance in individuals never being treated may impact people’s ability to respond well to therapy, when they will become eligible to initiate it.
If resistance in this population is observed, it means that some proportions of people that are receiving treatment for HIV/AIDS are not taking their medication correctly, therefore are developing resistance that subsequently gets transmitted to previously uninfected people.
As a result, these newly infected people, who had the bad lack to be infected with a virus already resistant to some of the drugs used to treat HIV, are at great danger to not respond to first line therapy, despite never being treated.
In limited resource settings, where the selection of drugs for treating HIV is limited, it is crucial to ensure the long term effectiveness of available drugs.
Why did resistance increase with the expansion of HIV treatment?
Scale up of antiretroviral therapy in low and middle income countries started in 2003 and has been expanded at an incredible pace. From 2003 and 2010 antiretroviral use in low and middle income countries increased 26 fold, and more than 8 million people were receiving antiretroviral therapy at the end of 2011.
Now, it is somehow intuitive that resistance in an inevitable consequence of expanded availability of drugs for HIV.
The more people are on therapy, the more people will fail therapy. The more people fail therapy, the more people are likely to fail therapy carrying a resistant virus, resulting in an increase in transmission of resistance to previously uninfected people. This means that the relative contribution to new infections from people that are failing ART with HIVDR will increase and we will have an increased proportion of new infections that are resistant among those which are not averted.
On the other hand, with an even greater expansion of therapy and antiretrovirals used for prevention, HIV incidence in populations can decrease, resulting in a reduction of the actual number of new resistant infections. This is indeed a complicated issue.
What are the regions of the world where drug resistance is most common and most on the rise? Why is this the case?
Available data suggest that between 10% and 17% of untreated individuals in Europe, North America, Australia and Japan carry drug resistance HIV to at least one antiretroviral drug.
While – on average – resistance is less prevalent in low and middle income countries than in industrialized countries, its increasing prevalence requires vigilance.
Findings from the Report that the World Health Organization has just released indicate that rapid expansion of HIV treatment with antiretrovirals in low and middle income countries, has so far resulted in an overall increase of observed levels of HIV drug resistance, reaching a peak of:
- Among untreated recently-infected individuals: 3.4% in 2009
- Among individuals about to initiate ART (chronically infected): 6.8% in 2010
Finding from our Lancet paper suggest that, in the African region, East Africa had the highest estimated rate of increase at 29% per year since rollout, with an estimated prevalence of HIV-1 drug resistance at 8 years after rollout of 7·4%.
We recorded an annual increase of 14% in southern Africa and a non-significant increase of 3% in west and central Africa.
There is a difference why drug resistance tends to be higher in richer countries; this is because people have had access to ART much longer in these countries - and in the early days of ART they used mono or dual therapy which predisposed to emergence of HIV drug resistance.
People in low and middle income countries have started ART scale up using highly active antiretroviral therapy and predominantly have been using fixed dose combinations, which are much easier to take. This is one possible important explanation for the lower levels of resistance in the South.
What happens to a patient if he/she is resistant to a drug? How many other drug options are there and is there a known case, where a patient is resistant to all known HIV drugs?
Patients with resistance to antiretrovirals used for first line regimen are less likely to respond to therapy, and therefore will need to be switched to more costly and toxic second-line regimens.
People living in resource limited countries have limited selection of drugs to treat HIV and therefore it is vital that national HIV programme step up their effort to monitor its evolution and ensure the long term effectiveness of available drugs.
Do you think this resistance will become a problem in other parts of the developing world or will it be confined to Sub-Saharan Africa?
One cannot predict the future. With the expanded access of antiretrovirals in low and middle income countries, it is certainly possible that HIV drug resistance will increase further in the future.
This is why strong HIV drug resistance surveillance is vital for national HIV programmes in order to monitor resistance evolution in a timely manner and take the necessary action to preserve the future effectiveness of antiretrovirals.
Are there any ways that we can halt or stop HIV drug resistance?
Although, as we just said, the expansion of treatment leads inevitably to some increase in resistance, this rise can be fast or slower, depending how HIV clinics in low and middle income countries manage to limit resistance emergence.
A sub-optimally performing HIV clinic (with poor retention rate, high rate of loss to follow up, drug stock out interruptions, poor adherence support) can lead to high rate of resistance in patients on therapy, who can afterwards transmit the resistant virus to previously uninfected individuals. These individuals infected with a resistant virus may not respond as well to therapy, depending on the kind of resistance that has been transmitted. HIV programmes need to limit this from happening.
The World Health Organization HIV drug resistance report that was just released indicates a disparity in performance among the >2000 ART clinics surveyed in 50 different limited resource countries:. some clinics perform better than others in minimizing emergence of HIV drug resistance in patient on therapy.
There are several things that we can do to help minimize resistance and preserve the future effectiveness of antiretrovirals. We need to make sure that clinics do not experience drug stock out. We need to make sure that people starting treatment stay on their treatment, are not lost of follow up and that they take their pills correctly.
We can help them to do this by using simplified, robust regimens and easy to take fixed dose combinations. We can also help by improving monitoring of patients to make sure we identify patients failing therapy soon after failure and we change their drugs to second line regimen in a timely manner.
Finally, it is very important that routine surveillance be done to look at rates of transmitted and acquired HIV drug resistance.
Why is it important for countries to survey for drug resistance, and how can they use this information to better address the AIDS epidemic?
In most low and middle income countries HIV drug resistance testing of individual patients is not available due to its very high cost. Knowing about drug resistance in untreated populations helps countries and policy makers to choose the best drugs for:
- future first line treatment of people infected with HIV and in need of therapy
- prevention of mother to child transmission of HIV
- pre- and post-exposures prophylaxis
Knowing levels and patterns of resistance in people on therapy, helps us to understand whether second line regimens are likely to be effective for the majority of patients failing first line ART.
Surveillance also informs a country how well its ART programme is functioning in minimizing emergence and transmission of drug resistant virus.
Do you think that the ART therapy could be slightly modified so that the drug-resistant HIV can be overcome, or do you think we need new therapies altogether?
Data so far show that when people fail first line regimens, the currently used second line ART (ritonavir-boosted protease inhibitor-based regimen) should be effective for the vast majority.
In addition, given the relatively low level of resistance observed in untreated individuals in low and middle income countries, the vast majority of people with HIV drug resistance will be able to respond well to currently available first line drugs. If we continue to scale up HIV drug resistance surveillance and optimize programme functioning, currently available therapies should be expected to work for a long time to come.
How do you think HIV therapy will progress over time?
Over time, new and improved drugs and combinations will be available and we will have a wider range of sequencing options. We are already seeing this with the advent of medications given as fixed dose combinations which make taking pills easier and medications with far fewer adverse effects.
It has recently been in the news that anti-HIV drugs may potentially pass to babies in the womb. Would you like to comment on this?
We know that transmission from mother to the baby can occur any time during pregnancy, labour and breastfeeding. At any of this phases the fetus and the baby can be exposed to maternal antiretroviral drugs used to prevent mother- to- child- transmission (PMTCT) such that resistance can develop as high as in the 50% of the infants that become infected despite the use of antiretrovirals.
However it has been shown that the prevalence of resistance, particularly to NNRTI, can be reduced with combination regimens, including HAART. The exact degree by which each component of the PMTCT interventions contribute in selecting resistance in infants is not entirely known yet, however it is expected that as PMTCT will be scaled up further by HIV programmes the majority of the babies who will acquired HIV despite PMTCT will be more likely to carry resistance to antiretrovirals, therefore this is something which deserve attention and active surveillance.
Is there anything else you’d like to add?
I would like to say that resistance can be a serious threat and that without continued and increased national and international efforts, rising HIV drug resistance could jeopardize a decade-long trend of decreasing HIV/AIDS-related morbidity and mortality in low- and middle-income countries. National policy makers and international donors should step up their effort to monitor its evolution in a timely manner. This is a global responsibility if we want to win the fight against HIV/AIDS.
Where can readers find more information?
About Dr. Silvia Bertagnolio
Silvia Bertagnolio received her M.D from the School of Medicine “University La Sapienza” in Rome, Italy (1997), and became specialized in Infectious Diseases in 2001 at the Catholic University in Rome.
She spent few years of clinical practice as an infectious disease physician at the University Hospital in Rome, and several months in Africa and Asia working on malaria. In 2003, Dr Bertagnolio moved to the World Health Organization in Geneva, at the time when antiretrovirals were just starting to become available in low- and middle-income countries and when many feared that drug resistance would have seriously threaten the success of ART scale up in low and middle income countries.
Since then, Dr. Bertagnolio has being working for the World Health Organization leading the HIV Drug Resistance work and has traveled extensively in over fifty countries to assist National HIV Programmes to build HIV Drug Resistance Surveillance systems and interpret their data; she has also coordinated the establishment of the Global HIVDR Laboratory Network.
Dr. Bertagnolio is an expert on HIV/AIDS and related infection and has a special interest in resistance epidemiology, in particular in low and middle income countries. Her scientific contributions include work on the surveillance and monitoring of resistance, including determinants of resistance in limited resource settings. Recently, Dr Bertagnolio has been in charge of the development of the first World Health Organization Report on HIV Drug Resistance in low and middle income settings.