Although much progress has been made in preventing and treating HIV infection, critical challenges in our response to the HIV epidemic still remain.
These are, amongst others, finding a vaccine, finding a cure and implementing proven therapies for prevention and treatment. Here we focus on the progress being made in finding a cure. In the past couple of years, there have been several very exciting and promising observations that give us hope that both functional and sterilising cures are within our reach.
Functional vs sterilising
Firstly, what do we mean by functional and sterilising cures? A functional cure (or HIV remission) is when a patient with HIV infection is able to contain the virus, i.e. maintain an undetectable viral load, without the need for continued anti-retroviral treatment (ARVs). This differs from the traditional sterilising cure, which requires that the organism is completely eliminated.1 HIV is different from most infections because once it is established in the body, the virus remains for life, continually replicating. This is referred to as the latent reservoir. A cure for HIV must find a way to safely eliminate this reservoir.2
Mississippi baby
The case of the ‘Mississippi baby’ is the first reported HIV functional cure in an HIV-infected baby using drugs active against HIV. The baby was infected in the womb of the mother, although the exact time of infection is difficult to ascertain. The mother received no antenatal care and only presented at a health facility at delivery when her HIV-positive status was established. Dr Hannah Gay, a paediatric HIV specialist, started the newborn on HIV treatment with three drugs at 31 hours of life and continued the treatment until the baby was 18 months old. The baby and mother were then lost to follow-up medical care, but were traced five months later, when the mother reported that she had stopped administering ARVs to the baby. When the baby was re-tested, it was found that she was free of HIV. The baby is now three-years old, is still in follow-up care and remains free of HIV. 3
The Berlin patient
Another report of a HIV ‘cure’ was in an adult. Timothy Brown, also known as the ‘Berlin patient’, was HIV-infected and had leukaemia (cancer of the bone marrow). Several cancer treatments failed and Brown elected to have a bone marrow transplant to treat his cancer in 2007. The doctor selected a donor with a rare genetic mutation that turns off a cell receptor known as CCR-5. HIV needs this receptor to enter CD4 T-cells in order to cause infection. Brown’s cancer went into remission after two bone marrow transplants. In addition, the transplant replaced his immune system with one that could now fight HIV infection. He no longer needs to take ARVs and his tests for HIV are no longer positive. 4
Cure by stem-cell transplant
Recently, we learned of two cancer patients who were functionally cured of HIV following stem cell transplants (a new type of bone marrow transplant) to treat their cancer. Both patients have no detectable HIV several weeks after stopping HIV treatment.5 Further long-term follow-up is required for these two patients to see whether the virus reappears and a deeper understanding of the way in which the virus is cleared from the body is needed. Unlike the Berlin patient, whose new immune system was resistant to HIV infection, stem cells can be re-infected with HIV if re-exposed to the virus.
Not for everyone
Although these reports are exciting and give hope that a cure for HIV infection is possible, bone marrow transplants are not suitable for use in every patient. It is an expensive procedure that requires specialised care and results in death in about 20% of cases. Finding a matched donor, with the required genetic mutation, is also extremely difficult and the drugs used before and after the marrow transplant are associated with severe side effects and are not easily accessible in low and middle income countries.
Elite Controllers
We have also observed natural clearance of HIV in very rare instances (less than 1% of patients infected with HIV) in patients we refer to as ‘long-term non-progressors’ or ‘Elite Controllers’. These individuals are able to control HIV to undetectable levels for a long time (more than 20 years) and have a normal CD4 count without ARV treatment. Extensive studies are underway to find suitable treatments that replicate this effect in the majority of infected individuals.
Early ARVs
Starting ARVs during early HIV infection might achieve an undetectable viral load result because treatment preserves immune responses, reduces HIV in viral reservoirs, and decreases chronic immune activation. A cohort in Thailand has shown that very early treatment – even before HIV antibodies can be detected – leads to a substantial reduction in the size of the latent HIV reservoir. However, more long term follow-up of this cohort is needed. 6
VISCONTI
Data in adults that most closely resembles that of the Mississippi baby comes from the VISCONTI (Viro-Immunological Sustained CONtrol after Treatment Interruption) study undertaken by the Agence Nationale de Recherche sur le Sida (ANRS). In this study, 14 out of 70 patients were able to control HIV replication by using ARVs, within 10 weeks of infection. The ARVs have been stopped and their viral load is still undetectable up to six years after treatment interruption.?7 Notably, most patients in the VISCONTI cohort did not have this experience.
Earlier treatment initiation
The report of the Mississippi baby and the Thai and VISCONTI cohorts suggest that starting HIV treatment very early following HIV infection, especially in newborns and adults, could help to achieve HIV elimination, but more research is needed. It is also challenging to identify adults who have been recently infected. As research progresses, we will also need to balance side effects associated with early ARV treatment initiation in otherwise healthy individuals with the potential benefits of viral eradication.
For now all newborns and adults started on ARVs should continue treatment until more information and guidance is obtained. Given the new WHO guidelines released this year that recommend ART initiation when the CD4 count is <500 cell/mm3, many more individuals will require earlier treatment than before. Earlier treatment can also prevent HIV transmission which carries an additional public health benefit.
Important clues
We need to recognise that each of these cases provide important signals and clues for further research. A lot more research will have to be undertaken before these observations can be translated into strategies for curing HIV infection in a broader set of patients. This research could take several years, and it might be decades before this will be available as routine care.
For now it’s business as usual
Efforts to reduce vertical transmission such as prevention of unwanted pregnancies and screening of pregnant women for HIV, should continue as per current Department of Health (DoH) and World Health Organisation (WHO) guidelines. Similarly, treatment of adults with AIDS should be in accordance with current DoH and/or WHO guidelines.
Dr Halima Dawood is a senior scientist with CAPRISA
Prof. Quarraisha Abdool Karim is the Director of CAPRISA and chairperson of SANAC’s Prevention Technical Task Team
NOTES
- Lewin SR. A cure for HIV: where we’ve been, and where we’re headed. The Lancet 2013; 381:2057-58.
- Laird GM, Eisele EE, Rabi SA, Lai J, Chioma S, et al. (2013) Rapid Quantification of the Latent Reservoir for HIV-1 Using a Viral Outgrowth Assay. PLoS Pathog 9(5): e1003398. doi:10.1371/journal.ppat.1003398
- Persaud D, Gay H, Ziemniak C, et al. Functional HIV cure after very early ART of an infected infant. 20th Conference on Retroviruses and Opportunistic Infections. March 3–6, 2013. Atlanta, GA, USA. 48LB
- Hutter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 Delta32/ Delta32 stem-cell transplantation. N Engl J Med 2009; 360: 692–98.
- Henrich T et al. In depth investigation of peripheral and gut HIV-1 reservoirs, HIV-specific cellular immunity, and host microchimerism following allogeneic hematopoetic stem cell transplantation. 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Kuala Lumpur, abstract WeLBA05, 2013.
- Ananworanich J, Vandergeeten C, Chomchey N, et al. Early ART Intervention Restricts the Seeding of the HIV Reservoir in Long-lived Central Memory CD4 T Cells. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, March 3-6, 2013. Abstract 47.
- Sáez-Cirión A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, et al. (2013) Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study. PLoS Pathog 9(3): e1003211. doi:10.1371/journal.ppat.1003211.