Through time: the breakthroughs that changed the course of HIV treatment
This has been a landmark year for HIV treatment; a seven-year study confirmed that taking ART can prevent transmission between gay couples and a second patient has been effectively cured of HIV after receiving a stem cell transplant as a cancer treatment. Allie Nawrat tracks progress in the decades-long quest to effectively prevent, treat and attempt to cure the disease.
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Human immunodeficiency virus (HIV) spreads by attacking the body’s immune system, particularly CD4 T cells. It can destroy so many of these cells that the body cannot fight off infections, meaning patients suffer from many severe, opportunistic infections. Once a patient has fewer than 200 CD4 cells per cubic millimetre of blood, they are classified as having acquired immunodeficiency syndrome (AIDS).
Although HIV and AIDS were prevalent in the developing world throughout the 1900s, it only began to emerge as an epidemic in the developed world, and particularly the US, in the 1970s.
FDA approves first medication for AIDS
Early efforts against the HIV epidemic focused on understanding how the condition spreads, rather than treating the symptoms and preventing deterioration. However, in the late 1980s this began to change, and in March 1987, the US Food and Drug Administration (FDA) approved the first treatment for AIDS, AZT.
AZT is a form of antiretroviral therapy (ART) called a nucleoside reverse transcriptase inhibitor (NRTIs), which stops HIV using the reverse transcriptase enzyme to build HIV DNA and therefore prevents the virus infecting more cells.
Originally developed as an anti-cancer drug, National Cancer Institute scientists discovered its potency and efficacy in patients with HIV and filed for a patent in 1985.
An FDA advisory committee voted ten to one to recommend its approval only 25 months after the first demonstration of efficacy. This drug was later approved for children with AIDS in 1990 and then prescribed for pregnant women to prevent transmission to new-borns in 1994.
Simultaneously, the FDA created a new fast-track approval for HIV/AIDS drugs, which led to multiple approvals of drugs either slowing the progression of the disease or treating associated conditions.
1995 - 1996
Combatting drug resistance by combining ART
Roche’s saquinavir was approved by this same FDA accelerated programme in 1995, making it the first protease inhibitor (PI) available for HIV/AIDS patients. Protease enzymes are used by HIV to replicate itself; saquinavir binds to the active site of the viral protease, preventing the virus’ maturation and infection of more cells.
The same year researchers discovered that the HIV virus was highly susceptible to mutation, meaning it was beginning to develop resistance to approved ARTs.
Therefore, only a few months after its initial approval, the FDA authorised saquinavir to be used in combination with NRTIs like AZT in an attempt to mitigate HIV’s drug resistance. Roche’s drug was also approved to be prescribed with AbbVie’s ritonavir, another PI on the market from 1996.
This dramatically altered how HIV/AIDS was treated as it led to an age of effective multi-drug combination therapy, which is known as Highly Active Antiretroviral therapy (HAART).
The approval of Boehringer Ingelheim’s nevirapine, the first non-nucleoside reverse transcriptase inhibitor (NNRTI), in 1996 provided another ART type for inclusion in HAART. Therefore, helping to combat continuing drug resistance to the NRTI-PI combinations. Similarly to NRTIs, NNRTIs inhibit the reverse transcriptase, just in a slightly different way.
According to the US Centers for Disease Control and Prevention (CDC), the number of deaths from AIDS declined by 63% between 1995 and 1998 from 50,628 to 18,851, meaning AIDS was no longer the leading cause of death in the US. This impressive reduction in mortality rates has largely been attributed to this new combined, HAART approach; broad access to HAART was one core commitment of the reauthorized CARE Act.
Making ARTs available in developing countries
Despite this impressive headway in HIV/AIDS treatments, there remained serious barriers to widespread use of ARTs in the developing world; the core issue being their price. This led to the United Nations’ Programme on HIV/AIDS, known as UNAIDS, establishing a joint initiative with the World Health Organization (WHO) to persuade five pharmaceutical companies to reduce the price of their ARTs in developing countries.
According to the International Centre for Trade and Sustainable Development, in May 2000, Boehringer Ingelheim, Bristol-Myers Squibb, Roche, Glaxo-Wellcome and Merck agreed to slash HIV/AIDS drug costs by as much as 80%.
US President Bill Clinton supported this effort by issuing an executive order to support developing countries in both importing and developing generic versions of ARTs. In 2003, newly inaugurated US President George W Bush further built on this commitment by creating the President’s Emergency Plan for AIDS Relief (PEPFAR).
The WHO and UNAIDS confirmed in 2005 that an estimated 700,000 more people had access to ARTs as a result. Under PEPFAR, by 2009, the FDA had approved 100 drugs for use in combating HIV/AIDS outside of the US; 29 were new drugs and 71 were generics.
Bone marrow transplants emerge as a potential cure
In 2007, a US-born HIV patient called Timothy Ray Brown – known as the Berlin patient - underwent a stem cell transplant to treat his acute myeloid leukaemia. His Berlin-based doctors chose a donor who had screened positive for a homozygous CCR5-delta32 mutation; since the majority of HIV cannot enter a cell without a functional CCR5 gene, this donor was naturally immune to HIV.
Following the bone marrow transplant, Brown stopped talking the ARTs he had been taking since 1995; three months later the levels of HIV in his body had plummeted to undetectable levels and his CD4 T cell count increased. His genotype had actually changed from heterozygous and homozygous, regarding the CCR6-delta32 allele.
This was a breakthrough results since “discontinuation of ART typically leads to a rapid rebound of HIV load within weeks,” according to a published report of the patient’s experience in the New England Journal of Medicine.
The virus has never rebounded in Brown, meaning he has been in remission from HIV for 12 years and is considered to be cured. Although a stem cell transplant is a risky, extreme option for HIV patients without cancer, the German researchers noted their findings “should encourage further investigation of the development of CCR5-targeted treatment options.”
Exploring how antiretroviral therapy prevents transmission
Various studies completed throughout the 2010s found that treatment with antiretroviral therapy reduced the risk of spreading the infection with HIV-negative partners; this was the case for both homosexual and heterosexual couples.
The HIV Prevention Trials Network’s HPTN052 study found that only one case of transmission from a HIV patient to their partner in 886 couples over two years; this was approximately 96% lower than the placebo group.
The study’s results were so conclusive regarding the effectiveness of antiretroviral treatment to prevent transmission between partners, the study was stopped early and all participants were invited to join the drug group. In 2011, the Science journal named this study ‘breakthrough of the year.’
These findings were corroborated by the Partners study. There were no cases of transmission from a HIV-positive patient, who was undergoing antiretroviral therapy and had an undetectable viral load, to their HIV-negative partner within 972 gay couples and 548 heterosexual couples.
The first, four-year phase of this study, which was completed in 2014, studied heterosexual and gay couples, whereas the second seven-year phase focused only on homosexual couples and was published in the Lancet in June 2019.
Study author and University College London professor of infectious disease Professor Alison Rodger said: “This powerful message can help end the HIV pandemic by preventing HIV transmission, and tackling the stigma and discrimination that many people with HIV face.”
Second patient achieves HIV remission after stem cell transplant
In March 2019, University College London (UCL) and Imperial College London announced that a patient known as the ‘London patient’ had also been cleared of HIV following a stem cell transplant to treat Hodgkin’s lymphoma.
The donor, like the donor in the first, Berlin patient case, had two copies of the CCR5-delta32 genetic mutation. The patient stopped ART 16 months following the transplant and his blood viral load remained undetectable 18 months later.
University of Cambridge Professor Ravindra Gupta, who led the study while working at UCL, said: “By achieving remission in a second patient using a similar approach, we have shown that the Berlin Patient was not an anomaly, and that it really was the treatment approaches that eliminated HIV in these two people.”