Human Immunodeficiency Virus (HIV) is a diploid, enveloped single-stranded retrovirus that integrates into host chromosomes and replicates within the human body. The virus initially infects macrophages and helper T-cells leading to an acute mononucleosis-like syndrome and can progress to affect the host’s immune system leading to Acquired Immunodeficiency Syndrome (AIDS). Since its discovery in 19811, HIV research and treatment has made many advances, but management has been limited by legal restrictions on organ transplantation in those with HIV. However, in 2013 the HIV Organ Policy Equity (HOPE) Act2,3 was passed and in March 2016, a multidisciplinary team from Johns Hopkins Hospital performed the first organ transplant in the United States from a HIV donor to a HIV-positive recipient4. The decision for transplantation is patient-specific and certain criteria must be met before a HIV-positive individual can be considered for organ transplantation. Overall, the recent advances in HIV-to-HIV organ transplantation have drastically improved prognosis and quality of life for individuals with HIV.

Introduction 

Human Immunodeficiency Virus (HIV) is a diploid, enveloped retrovirus that integrates into host chromosomes and replicates within the human body 5. The virus infects CD4+ T cells and macrophages leading to an acute mononucleosis-like syndrome and can progress to affect the host’s immune system leading to Acquired Immunodeficiency Syndrome (AIDS) 5. Since its discovery in 19811, HIV research and treatment has made many advances, but management has been limited by legal restrictions on organ transplantation in those with HIV in the United States. However, in 2013 the HIV Organ Policy Equity (HOPE) Act 2,3 was passed and in March 2016 a multidisciplinary team from Johns Hopkins Hospital performed the first organ transplant in the United States from a HIV donor to a HIV-positive recipient 4. The Hopkins team was inspired by success stories from South Africa, the United Kingdom, Canada and Switzerland.

HIV and Organ transplantation

Transmission of HIV may be via blood, semen, breast milk, or vaginal fluid. Risk factors for transmitting HIV include: a high viral load, ulcerated sexually transmitted infections, uncircumcised penis, receptive anal intercourse, unprotected sexual intercourse, multiple sexual partners and intravenous drug abuse with contaminated needles1,5. 

HIV enters the body and infects macrophages and helper T-cells5. The virus enters these cell via interactions of the virion envelope glycoproteins and chemoreceptors. Once inside, the virus uncoats and integrates into the DNA of the host via reverse transcriptase5. Reverse transcriptase converts the viral single-stranded RNA to double-stranded DNA which can then be integrated into the host cells. From there, thevirus may remain latent or replicate. The acute phase of HIV may be asymptomatic or may present with a mononucleosis-like syndrome known as “acute retroviral syndrome”5. Signs and symptoms may include: fever, sore throat, rash, myalgia, headache, cervical lymphadenopathy, painful mucocutaneous ulcers, and aseptic meningitis1. The acute phase involves rapid replication with high viral RNA levels which typically stabilise around six months’ post-infection. Following transmission and the acute phase, patients develop chronic HIV which is marked by a CD4 count that is inversely proportional to the viral load. This phase is usually asymptomatic and with adequate treatment, should not progress to AIDS. 

The diagnosis of HIV is initially made using an enzyme-linked immunosorbent assay (ELISA) screening test for HIV antibodies. The ELISA screening test can produce false negatives up to 6 months’ post-exposure. The diagnosis of HIV by ELISA can be confirmed by using Western blotting. Following diagnosis, viral load and CD4 count can be assessed using quantitative polymerase chain reaction (PCR). Genotype testing can be done to determine the HIV strain. Finally, drug-resistant testing should be performed as 20 percent of patient are resistant to at least one antiretroviral drug. 

HIV can remain latent for up to ten years, during which time it continues to replicate within lymph nodes in the body. When a patient’s CD4+ T cell count drops below 200 cells/mm3 or if an AIDS-defining illness is present, regardless of the CD4+ count, the patient is considered to have AIDS. AIDS-defining illnesses include: Pneumocystis jiroveci pneumonia, toxoplasmosis, Mycobacterium avium infection, Kaposi’s sarcoma and lymphoma. AIDS is associated with an increased risk of these opportunistic infections and a higher mortality rate than HIV1,5.

HIV treatment has advanced tremendously since its discovery in 19811. The introduction of highly active antiretroviral therapy in 19963,6 has allowed many HIV patients to share life expectancies compared to the non-infected population. However, chronic conditions such as hepatitis and HIV-associated nephropathy, tend to progress more rapidly in HIV patients, resulting in an increased need for organ transplantation. Up to one-third of patients with HIV will develop chronic kidney disease5. This can be related to the virus itself, a hepatitis co-infection, HIV-associated nephropathy, antiretroviral treatments, or co-morbidities such as diabetes and hypertension3. 

Until recently, a diagnosis of HIV was a contraindication for organ transplantation7. The expert opinion was that the requirement of immunosuppressant therapy to prevent organ rejection would expedite the development of AIDS in patients with HIV. This view began to change in 19987 and HIV-negative patients have since been allowed to serve as donors for HIV-positive recipients. The HIV Solid Organ Transplant Multi-Site Study of kidney transplantation demonstrated that 3-year survival rates in HIV-positive patients was 88% which exceeded older non-HIV patients by four percent8. Similar data was seen in liver transplantation. In either case, no progression of HIV was seen and the only major difficulty was related to more graft rejection in HIV-positive individuals. Overall, transplantation proved to yield a better prognosis. Studies like this provided confidence and reassurance for those considering transplant, resulting in a fourfold increase in liver transplantations and threefold increase in kidney transplantations between 2004 and 2013 to HIV-positive patients the United States8. 

Unfortunately, the waiting list for organ transplantation still posed a problem for many. At any given time, there is approximately 122,000 people on the United States transplant waiting list3,4. Consequently, many patients die awaiting a transplant. Experts in the field recognized that the waiting list for HIV-positive patients would greatly decrease if HIV-positive patients could serve as donors. The development of HIV-to-HIV transplantation was successfully performed first in South Africa where twenty-seven HIV-positive individuals received kidney transplants. Overall patient survival was 84% at 1 year and 3 years, and 74% at 5 years. Graft survival was 93%, 84% and 84%, respectively, with an 8% rejection rate at one year9. 

But, since 1984 the National Organ Transplant Act has prevented HIV-positive patients to act as donors in the United States. This ban was reversed in 2013. The HOPE was passed by Congress and signed into law by President Obama on November 21, 20132,3. The HOPE Act allowed the harvesting of HIV-positive organs and the transplantation of these organs to HIV-positive recipients. This effort was largely led by Dr Dorry Segev3, the director of the HIV transplant program at Johns Hopkins Hospital, who then went on to lead a team of surgeons in the first-ever successful transplant of liver and kidney from a deceased HIV-positive donor to a HIV-positive recipient in the United States. 

Along with South Africa and the United States, Canada has also attempted HIV-to-HIV transplantation. Between 2005 and 2009, 39 potential HIV-infected donors died out of 335,793 hospital deaths in Canada. Canadian researchers went on to explore the option of using HIV-positive donors for transplantation. The first Canadian HIV-to-HIV kidney transplantation took place in January 201610,11. 

HIV treatment has advanced tremendously since its discovery in 19811. The introduction of highly active antiretroviral therapy in 19963,6 has allowed many HIV patients to share life expectancies compared to the non-infected population. However, chronic conditions such as hepatitis and HIV-associated nephropathy, tend to progress more rapidly in HIV patients, resulting in an increased need for organ transplantation. Up to one-third of patients with HIV will develop chronic kidney disease5. This can be related to the virus itself, a hepatitis co-infection, HIV-associated nephropathy, antiretroviral treatments, or co-morbidities such as diabetes and hypertension3. 

Until recently, a diagnosis of HIV was a contraindication for organ transplantation7. The expert opinion was that the requirement of immunosuppressant therapy to prevent organ rejection would expedite the development of AIDS in patients with HIV. This view began to change in 19987 and HIV-negative patients have since been allowed to serve as donors for HIV-positive recipients. The HIV Solid Organ Transplant Multi-Site Study of kidney transplantation demonstrated that 3-year survival rates in HIV-positive patients was 88% which exceeded older non-HIV patients by four percent8. Similar data was seen in liver transplantation. In either case, no progression of HIV was seen and the only major difficulty was related to more graft rejection in HIV-positive individuals. Overall, transplantation proved to yield a better prognosis. Studies like this provided confidence and reassurance for those considering transplant, resulting in a fourfold increase in liver transplantations and threefold increase in kidney transplantations between 2004 and 2013 to HIV-positive patients the United States8. 

Unfortunately, the waiting list for organ transplantation still posed a problem for many. At any given time, there is approximately 122,000 people on the United States transplant waiting list3,4. Consequently, many patients die awaiting a transplant. Experts in the field recognized that the waiting list for HIV-positive patients would greatly decrease if HIV-positive patients could serve as donors. The development of HIV-to-HIV transplantation was successfully performed first in South Africa where twenty-seven HIV-positive individuals received kidney transplants. Overall patient survival was 84% at 1 year and 3 years, and 74% at 5 years. Graft survival was 93%, 84% and 84%, respectively, with an 8% rejection rate at one year9. 

But, since 1984 the National Organ Transplant Act has prevented HIV-positive patients to act as donors in the United States. This ban was reversed in 2013. The HOPE was passed by Congress and signed into law by President Obama on November 21, 20132,3. The HOPE Act allowed the harvesting of HIV-positive organs and the transplantation of these organs to HIV-positive recipients. This effort was largely led by Dr Dorry Segev3, the director of the HIV transplant program at Johns Hopkins Hospital, who then went on to lead a team of surgeons in the first-ever successful transplant of liver and kidney from a deceased HIV-positive donor to a HIV-positive recipient in the United States. 

Along with South Africa and the United States, Canada has also attempted HIV-to-HIV transplantation. Between 2005 and 2009, 39 potential HIV-infected donors died out of 335,793 hospital deaths in Canada. Canadian researchers went on to explore the option of using HIV-positive donors for transplantation. The first Canadian HIV-to-HIV kidney transplantation took place in January 201610,11. 

With regards to surgical transplantation, the operations for HIV-to-HIV transplantations are nearly identical to non-HIV transplantations3. However, the pre-operative matching process for organ transplantation is extensive. First and foremost, donor and recipient HIV strains must match. There are two major types of HIV: HIV-1 and HIV-2. HIV-1 is more virulent and common worldwide, whereas HIV-2 is mostly limited to West Africa. HIV-1 has four subtypes HIV-1 M Group, N group, O group, and P group, of which, Group M is the most common, accounting for greater than ninety percent of HIV-1 infections. Group M is further subdivided and its subtype B predominates in the United States, while subtype C predominates elsewhere12. 

Furthermore, transplant recipients must meet the National Institute of Health Multi- Site Study guidelines. Criteria include: CD4 count greater than 200 cells/mm3, viral load <50 copies/mL, no active opportunistic infections, and maintenance on a stable antiretroviral regime8,9. The above criteria refer to kidney transplant recipients. For liver transplant recipients, the CD4 count can be as low as 100 cells/mm3 and patients do not necessarily have to be on an antiretroviral regime at the time of transplant8,13. 

Other criteria for assessing compatibility between donor and recipient involves extensive review of antiretroviral treatment history, responses to previous treatment, compliance, resistance, and review of donor HIV RNA levels. Absolute exclusion criteria include: history of major malignancies and history of opportunistic infections8,13.

Post-operatively, the appropriate choice of antiretroviral therapy is crucial. In prescribing, one must consider the organ-specific toxicities and the potential interactions with post-transplant immunosuppressive therapy. The standard regimen for all HIV patients includes a combination of at least three antiretroviral drugs including nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs), integrase inhibitors, protease inhibitors (PIs), and entry inhibitors. In a study done in 2016 comparing HIV-positive and HIV-negative individuals undergoing kidney transplantation, the overall survival was 90% in both cohorts. However, HIV patients who went on to receive protease-inhibitors had a higher incidence of infection, graft rejection, and mortality compared to those patients who did not receive protease inhibitors as part of their post-transplantation regime. Consequently, the use of integrase inhibitors Ralegravir and Dolutegravir is preferred as these drugs have a low risk of potential drug interactions14.

Chugh et al., in 2010, estimated that 33.5 million individuals suffered from atrial fibrillation worldwide. This study found a general increase in AF-associated mortality over time and concluded "systematic, global surveillance of AF is required to better direct prevention and treatment strategies". The proposed device would assist in achieving such systematic and global surveillance of AF, particularly in rural and poverty-stricken areas. 

DISSCUSSION

The history of HIV is remarkable. Believing to have originated from primates in West Africa and transferred to humans via zoonosis, in just thirty-six years2, HIV has gone from being considered a death sentence, to being a manageable co-morbidity. When HIV was first discovered in humans, it was described as a curious collection of cases in a small population of drug users and homosexual men who presented with symptoms of Pneumocystis carinii pneumonia. Similar presentations began to be reported and the Centre for Disease Control and Prevention began to monitor for an outbreak of this undefined illness. In the media, AIDS (coined September 24th, 1982)3 was first known as Gay-related Immunodeficiency, or GRID. Human Immunodeficiency virus was then discovered a year later in 1983. A lot of research has been done since this time, which has helped to attenuate the stigmatization many HIV and AIDS patients once faced. 

The recent advancement in organ transplantation for HIV patients has drastically improved the overall survival in patients with HIV3,7. The eligibility of HIV-positive patients to act as donors helps to destigmatize those who were once limited by their diagnosis. In addition, all HIV-negative patients on the transplant waiting list benefit from the HOPE Act2,3, as their chances for receiving a transplant increase. Essentially, the HOPE Act allowed for the transplant pool to significantly increase in size, attenuating the organ shortage in the United States3. 

As discussed, many countries are now exploring the once uncharted territory of HIV-to- HIV organ transplantation10,11. The development of these new surgical techniques has helped to destigmatize HIV, to increase the lifespan in HIV patients with chronic disease, and to expedite the waiting list for transplantation in both HIV-positive and HIV-negative individuals.

Conclusion

Human Immunodeficiency Virus infection is more manageable than in the past. Continued investigation of this virus and its effects will yield more answers to the questions we still face. Thanks to the field of infectious disease, we now understand more about this infection which has allowed improved quality of life for patients who face this diagnosis. From highly active antiretroviral therapy6 to organ transplantation, there are now options for these individuals. 

The recent success of organ transplantation from HIV-positive donors to HIV-positive recipients has revolutionized the approach to HIV treatment and has opened new doors in organ transplantation worldwide. 

Nonetheless, continuing research is crucial to better understand HIV and address the ongoing issues with side effects to highly active antiretroviral therapy and graft rejection.

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