- Email: [email protected]
AIDS infection: The beginning of the end for today's greatest pandemic?
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ARTICLE IN PRESS
Rev Clin Esp. 2017;xxx(xx):xxx---xxx
Revista Clínica Española www.elsevier.es/rce
SPECIAL ARTICLE
HIV/AIDS infection: The beginning of the end for today’s greatest pandemic?夽 F. Gutiérrez Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital General Universitario de Elche, Universidad Miguel Hernández, Alicante, Spain Received 2 February 2017; accepted 18 April 2017
KEYWORDS HIV; AIDS epidemic; Antiretroviral therapy; HIV eradication; HIV cure
PALABRAS CLAVE VIH; Epidemia de sida; Terapia antirretroviral; Erradicación del VIH; Curación del VIH
Abstract Recently, there have been significant advances in the fight against human immunodeficiency virus, which have increased the hopes of definitively halting its dissemination and of starting the decline of the epidemic it has caused. Transmission of the infection was drastically reduced when infected patients were given antiretroviral treatments, which boosted the diffusion of treatments to middle- and low-income countries. Global therapy coverage has doubled in recent years; meanwhile the incidence of new infections has decreased. Various curative strategies are also actively being investigated, including those aiming to induce cell resistance to the infection through gene therapy and the elimination of latent virus reservoirs. This article reviews the current situation and future developments in terms of controlling the pandemic and, eventually, curing the infection. © 2017 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.
Infección por el VIH/sida: ¿El principio del fin de la primera gran pandemia contemporánea? Resumen En los últimos a˜ nos se han producido avances importantes en la lucha contra el virus de la inmunodeficiencia humana que hacen concebir esperanzas de que pueda detenerse definitivamente su diseminación y de que la epidemia que ha provocado entre en fase de declive. Se ha demostrado que el tratamiento antirretroviral de los pacientes infectados reduce drásticamente la transmisión de la infección, lo que ha impulsado la extensión de los tratamientos a los países de renta media y baja. La cobertura terapéutica a escala mundial se ha duplicado
夽 Please cite this article as: Gutiérrez F. Infección por el VIH/sida: ¿El principio del fin de la primera gran pandemia contemporánea? Rev Clin Esp. 2017. http://dx.doi.org/10.1016/j.rce.2017.04.004 E-mail address: gutierrez [email protected]
2254-8874/© 2017 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.
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F. Gutiérrez en los últimos a˜ nos y de forma paralela se ha reducido la incidencia de nuevas infecciones. Al mismo tiempo se están investigando activamente diferentes estrategias para la curación, entre ellas las encaminadas a inducir resistencia celular a la infección mediante terapia génica y la eliminación de los reservorios de virus latente. En este artículo se revisa la situación actual y las perspectivas futuras para controlar la pandemia y, quizá, curar la infección. © 2017 Elsevier Espa˜ na, S.L.U. y Sociedad Espa˜ nola de Medicina Interna (SEMI). Todos los derechos reservados.
Background The acquired immune deficiency syndrome (AIDS) pandemic is undoubtedly the most significant of modern times. Of all known viruses, the human immunodeficiency virus (HIV) has one of the highest lethality rates. Since its onset in 1981, HIV has caused the death of more than 30 million individuals. The most recent estimates by the World Health Organization (WHO) and the Joint United Nations Program on HIV and AIDS (UNAIDS) indicate that 37 million individuals are currently infected.1 Each year, 2 million new infections are produced, and more than 1 million individuals die from the disease worldwide. In the 35 years of struggle against AIDS, there have been major scientific advances that have been transferred in an exemplary fashion to real life. These advances have helped convert HIV infection into a controllable chronic disease. An important scientific milestone was the identification of HIV in 1983, only 2 years after declaring the first cases of AIDS in the US. Shortly thereafter, the virus’ genetic organization was discovered. Studies showed that the main targets of HIV were the T lymphocytes and that the most important cell receptor was the RCA-4 (CD4) protein, although the entry of the virus into the cells also required the binding to other proteins of the cell membrane, called coreceptors, whose natural ligands are different chemokines. The 2 main coreceptors of HIV are CCR5 and CXCR4, and most new infections are caused by viruses that use CCR5 to enter the cells (virus with R5 tropism).2 We know that activated T-CD4(+) lymphocytes are often infected, which is where transcription of the HIV genome is started. Within a few hours, massive viral replication occurs, with destruction of the infected cells.3 Over time, the progressive cell destruction leads to T-CD4(+) lymphopenia, with damage to the architecture of the lymph nodes and other lymphoid tissues, as well as immunoactivation and general dysregulation of the immune function. In a median of approximately 10 years, the patient develops severe immunodeficiency.3 There is, however, considerable heterogeneity in the outcomes of patients with the infection, ranging from rapid progression to the so-called elite controllers, a rare group of individuals who for years maintain spontaneous control over viral replication without treatment.4 Variants have also been described in the human genome that confer natural resistance to infection by this virus. The best characterized of these variants is a deletion of a gene segment of coreceptor CCR5 (CCR5-32), which
impedes penetration by the virus with tropism R5 in the lymphocytes.5 Individuals with this homozygous CCR5-32 variant (less than 1% of the white population) are highly resistant to HIV infection, even after repeated exposure to the virus.6
Achievements and limitations of antiretroviral therapy In the last 2 decades, increasingly effective antiretroviral drugs have been developed, and a continuous reduction in overall mortality for AIDS has been documented.7 The current antiretroviral therapy (ART) regimens can achieve virological suppression (defined by the inability to detect viruses in the blood using highly sensitive molecular techniques) in almost 90% of cases,8 which has translated in a growing proportion of patients who are virologically controlled. Thanks to the widespread use of prophylaxis with antiretrovirals during pregnancy, the vertical transmission of the infection has been practically eliminated in high-income countries.9 Since the first decade of the 21th century, international initiatives have been launched with public and private funds that, aligned with the WHO directives, have implemented ART programs in low to middle-income countries. Thus, in 2009, more than 30% of infected patients in Africa had access to treatment. Following an incessant increase in worldwide mortality from AIDS that exceeded 2.5 million deaths annually, since 2005, there has been a documented reduction in mortality from this cause, which continues to this day.1 The achievements of ART have undoubtedly been significant. However, long-term administration of antiretroviral drugs also has many disadvantages10---13 and does not eradicate the infection. Patients who are kept in a state of virological suppression with ART are known to have proviral DNA with replicative capacity. It has been shown that discontinuing ART in these patients is inevitably followed by a rebound in viremia due to the presence of cellular reservoirs of the virus.14 These reservoirs are rapidly established after the infection and mainly consist of lymphocytes infected with already integrated virus that enter a state of rest/latency.15 These lymphocytes with latent infection and without detectable replication represent a small proportion of the total infected lymphocytes (less than one per million) but have a long half-life (months-years). These cells do not express any viral marker or protein on their surface and are
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HIV/AIDS infection: The beginning of the end for today’s greatest pandemic? therefore not recognized by the immune system. Due to the absence of replication, these cells are also ‘‘invisible’’ to antiretroviral drugs.16 ART thereby prevents the progression but does not cure the infection.
The first steps toward a cure In 2009, news broke on what is currently the only documented case of a patient being cured of HIV: the so-called ‘‘Berlin patient’’.17 This patient was infected by HIV and developed acute myeloblastic leukemia. The patient underwent intensive chemotherapy to cure the leukemia and received a hematopoietic stem cell transplant from a donor homozygous for the CCR5-32 deletion. Before the transplantation, the ART was interrupted. The surprise was that, following transplantation, the patient continued to maintain undetectable plasma viral loads without ART. Although the HIV was exhaustively sought in the blood and tissues, there was no trace of the virus 10 years later. This case represents a proof of concept that an ablative hematologic therapy followed by transplantation with HIV-resistant cells could cure the infection. Unfortunately, bone marrow transplantation is a complex and costly procedure, which also requires the concomitant use of immunosuppressants that can cause adverse effects, including a greater risk of opportunistic infections, and it is therefore not a viable strategy for the general treatment of patients infected by HIV. Moreover, finding donors that are homozygous for CCR5-32 is difficult, because this genetic variant is present in less than 1% of the white population.6 The experience of the ‘‘Berlin patient’’ has opened the door to curative strategies based on gene therapy. One of the most promising initiatives is based on the possibility of obtaining HIV-resistant CD4+ lymphocytes in the laboratory using genetic engineering techniques. To this end, zinc finger nucleases (ZFN) designed to modify the gene of coreceptor CCR-5 are employed, deleting the 32 base pairs missing in the CCR5-32 deletion. Tebas et al. assessed the results of a clinical trial that infused these genetically modified CD4+ lymphocytes into patients with chronic HIV infection and good virologic control with ART.18 The procedure consisted of extracting lymphocytes from the patients using apheresis, which were then genetically modified in the laboratory and reinfused into the patients. After reinfusion, a significant increase in the number of circulating CD4+ lymphocytes and genetically modified CD4+ lymphocytes was observed. Subsequently, a subgroup of these patients had their ART suspended with the intent to allow the HIV to replicate. The study observed that the genetically modified lymphocytes survived better against the virus replication.18 The study’s positive results raise hopes about the future of gene therapy with this and other strategies aimed at inducing cell resistance to the infection through the elimination of genes that encode the coreceptor CCR5 and other key proteins in the entry process, such as the fusion peptide, a fundamental structure for producing the fusion between the HIV membranes and the target cell.19 Another of the strategies undergoing research for curing HIV is the so-called ‘‘shock and kill’’, which seeks to eliminate the viral reservoirs by activating and destroying the resting lymphocytes that contain integrated virus. There
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are several compounds that can reactivate the infected cells in a latent manner and induce the production of viral proteins. These compounds include histone deacetylase (HDAC) inhibitors, such as vorinostat, romidepsin and panobinostat.20,21 HDACs directly regulate the mechanism of HIV latency, inducing histone deacetylation in the virus integration sites. Histone acetylation translates into a transcription activation. Although the mechanism by which the HDAC inhibitors induce HIV reactivation in the resting lymphocytes is not entirely known, the inhibitors are believed to activate the HIV promoter sequence, inducing nucleosome hyperacetylation of the promoter sequence and suppressing the binding of HDACs to the HIV promoter sequence. The antilatency drugs studied so far have individually had a modest effect on the latent cellular reservoir. It is currently believed that a combination of 2 or more latencyreversing agents might be necessary to reduce the cellular reservoir and that it might also be necessary to boost the immune system so that it more effectively recognizes the infected cells and destroys them. This immune potentiation could hypothetically be conducted by ‘‘spurring’’ the cytotoxic lymphocytes to delete the reservoir cells where the HIV is reactivated, through therapeutic vaccines22 or with neutralizing antibodies. The use of broad spectrum neutralizing antibodies against viral proteins to clear viruses that are replicating and infected cells is one of the strategies that has raised the most expectations in recent years.23---25
Treatment as prevention: the hope for controlling the pandemic Pending new scientific milestones that accelerate the cure of the infection, relevant progress has taken place in recent years in epidemiological and clinical research, which have raised hopes about controlling the pandemic. One of these advances has been recognizing that ART is a powerful preventive tool, a finding that was considered the 2011 scientific breakthrough of the year by the journal Science.26 Before 2011, observational studies had been published on couples who were serodifferent for HIV (one member of the couple was infected and the other not), which indicated that HIV transmission was less likely if the infected partner was undergoing ART. The HIV Prevention Trials Network 052 study included 1763 serodifferent couples, mostly heterosexual, with a T-CD4 lymphocyte count in peripheral blood of 350---550 cells/L.27 The couples were randomized to 2 arms: immediate or deferred ART of the index case. In the latter case, therapy was postponed until the T-CD4 lymphocyte count dropped below 250 cells/L. The patients who began ART immediately had a 96% lower risk of transmitting the infection to their partner. In the deferred therapy arm, 27 individuals were infected in the deferred therapy group and only 1 was infected in the immediate therapy group.27 After determining these results, all infected patients who participated in the trial were offered ART (index cases). The study included follow-up of the couples for more than 5 years to assess the duration of the ART effect in preventing transmission. The efficacy lasted over time, and in fact there were no documented phylogenetically related transmissions when the index case maintained a stable undetectable HIV plasma viral load with ART.28
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4 Population studies have confirmed that increasing the number of treated individuals in a certain population can reduce HIV transmissions.29,30 In British Columbia (Canada), it was observed that as the populational viral load decreased (as a result of an increase in the number of infected patients with suppressed viral load, as a reflection of better antiretroviral coverage of the population), the number of new diagnoses of HIV infection also decreased.29 Similar results have also been observed in studies in Africa. A study in KwaZulu-Natal (South Africa) showed that high therapeutic coverage in the population with HIV infection in a specific geographical area was closely associated with the incidence of new infections in this area.30 The efficacy of ART in preventing HIV transmission has also been confirmed in a European study with hundreds of serodifferent couples.31 These results have led many experts in recent years to propose the strategy known as ‘‘Universal Test and Treat’’; in other words, performing the HIV infection detection test for the entire population and treating all those with the infection. This proposal is based on the fact that if we consider the scientific evidence that ART drastically reduces the risk of transmission, the more individuals who are treated, the less circulating virus there will be in the population and thus fewer infections. Various mathematical models have determined that universal voluntary screening for HIV, followed by immediate ART for detected cases, would be an effective strategy for eliminating HIV transmission, which would speed the transition from the current endemic phase to an elimination phase.32,33 Recognition of the efficacy of ART as a preventive tool has prompted its availability in low to middle-income countries. From 2010 to 2015, the therapeutic coverage doubled, from 23% to 46% of infected individuals worldwide.1 In its latest report, UNAIDS disseminated optimistic data on the evolution of the pandemic. In recent years, new infections in children have decreased 50%, and overall mortality has been reduced by more than 45%. These reductions have coincided with a considerable increase in access to ART, from 7.5 million individuals in 2010 to more than 18 million in 2015.1 With the goal of definitively stopping and reversing the spread of HIV and accelerating the epidemic’s decline, ambitious objectives have been set for 2020: diagnose 90% of those infected, treat 90% of those diagnosed and achieve stable undetectable HIV plasma viral loads in 90% of those treated.
Future prospects To control the AIDS pandemic, the scientific advances in the field of treatment for infected patients should be supplemented with research into new preventive strategies and the widespread use of those strategies whose efficacy has been well documented, such as the use of barrier methods. One of the areas of greatest interest in recent years has been pre-exposure prophylaxis with antiretroviral drugs in individuals with a high risk of infection through sexual relations.34---39 Studies performed to date have shown that pre-exposure prophylaxis in heterosexual men and women is safe and reduces the transmission of the infection, although the results have been mixed, depending on treatment adherence.36---39 Recently published results from 2 large clin-
F. Gutiérrez ical trials conducted with men who had sexual relations with men showed that pre-exposure prophylaxis lowered the risk of infection by 86%.34,35 The efficacy of pre-exposure prophylaxis has been confirmed in observational studies after implementing specific programs in various settings,40---42 and its predicted extension could be an additional strategy that significantly contributes to controlling the pandemic. The WHO predictions indicate that if the 90---90---90 objectives are achieved by 2020, the trend of the HIV/AIDS epidemic could be reversed. A 70% reduction is estimated in the incidence rate of new infections between 2010 and 2030, as well as a 65% reduction in mortality, which could be less than 500,000 deaths annually in 2030. Although the expectations of gaining control over the pandemic in the coming decades are high, we should recognize that there is still time to achieve the desired objectives: understanding how to cure the infection and definitively eradicating it. Although some curative strategies mentioned earlier are already being evaluated in clinical trials, it is expected that it will take some time until they can be applied in clinical practice. Meanwhile, the extension and globalization of preventive strategies, early diagnosis and current treatment could bring us steadily closer to the goal of ending one of the most significant contemporary pandemics.
Conflict of interests The author declares that he has no conflicts of interest.
References 1. UNAIDS. Fact sheet 2016 [consulted 30 Dec 2016]. Available in: http://www.unaids.org/en/resources/fact-sheet 2. Moore JP, Kitchen SG, Pugach P, Zack JA. The C.C.R5 and CXCR4 coreceptors ---central to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection. AIDS Res Hum Retroviruses. 2004;20:111---26. 3. Moir S, Chun TW, Fauci AS. Pathogenic mechanisms of HIV disease. Annu Rev Pathol. 2011;6:223---48. 4. Deeks SG, Walker BD. Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity. 2007;27:406---16. 5. Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber CM, et al. Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature. 1996;382:722---5. 6. Liu R, Paxton WA, Choe S, Ceradini D, Martin SR, Horuk R, et al. Homozygous defect in HIV-1 co-receptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell. 1996;86:367---77. 7. Gutiérrez F, Padilla S, Masiá M, Iribarren JA, Moreno S, Viciana P, et al. Clinical outcome of HIV-infected patients with sustained virologic response to antiretroviral therapy: long-term followup of a multicenter cohort. PLoS ONE. 2006;1:e89. 8. Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutiérrez F, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013;369:1807---18. noz E, Fernández-Ibieta M, 9. Prieto LM, González-Tomé MI, Mu˜ Soto B, del Rosal T, et al. Low rates of mother-to-child transmission of HIV-1 and risk factors for infection in Spain: 2000---2007. Pediatr Infect Dis J. 2012;31:1053---8.
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HIV/AIDS infection: The beginning of the end for today’s greatest pandemic? 10. Moreno S, Miralles C, Negredo E, Domingo P, Estrada V, Gutiérrez F, et al. Disorders of body fat distribution in HIV-1-infected patients. AIDS Rev. 2009;11:126---34. 11. Masia M, Bernal E, Padilla S, Graells ML, Jarrin I, Almenar MV, et al. The role of C-reactive protein as a marker for cardiovascular risk associated with antiretroviral therapy in HIV-infected patients. Atherosclerosis. 2007;195:167---71. 12. Masiá M, Padilla S, Alvarez D, López JC, Santos I, Soriano V, et al. CoRIS. Risk, predictors, and mortality associated with nonAIDS events in newly diagnosed HIV-infected patients: role of antiretroviral therapy. AIDS. 2013;27:181---9. 13. Gutiérrez F, Masiá M. The role of HIV and antiretroviral therapy in bone disease. AIDS Rev. 2011;13:109---18. 14. Chun TW, Davey RT Jr, Engel D, Lane HC, Fauci AS. Re-emergence of HIV after stopping therapy. Nature. 1999;401:874---5. 15. Marsden MD, Zack JA. Establishment and maintenance of HIV latency: model systems and opportunities for intervention. Fut Virol. 2010;5:97---109. 16. Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B, et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med. 2009;15:893---900. 17. Allers K, Hütter G, Hofmann J, Loddenkemper C, Rieger K, Thiel E, et al. Evidence for the cure of HIV infection by CCR5/32/32 stem cell transplantation. Blood. 2011;117:2791---9. 18. Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G, et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med. 2014;370:901---10. 19. Burke BP, Levin BR, Zhang J, Sahakyan A, Boyer J, Carroll MV, et al. Engineering cellular resistance to HIV-1 infection in vivo using a dual therapeutic lentiviral vector. Mol Ther Nucleic Acids. 2015;4:e236. 20. Rasmussen TA, Tolstrup M, Søgaard OS. Reversal of latency as part of a cure for HIV-1. Trends Microbiol. 2016;24:90---7. 21. Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012;487:482---5. 22. Mylvaganam GH, Silvestri G, Amara RR. HIV therapeutic vaccines: moving towards a functional cure. Curr Opin Immunol. 2015;35:1---8. 23. Lynch RM, Boritz E, Coates EE, DeZure A, Madden P, Costner P, et al., VRC 601 Study Team. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Sci Transl Med. 2015;7, 319ra206. 24. Caskey M, Klein F, Lorenzi JC, Seaman MS, West AP Jr, Buckley N, et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature. 2015;522:487---91. 25. Stephenson KE, Barouch DH. Broadly neutralizing antibodies for HIV eradication. Curr HIV/AIDS Rep. 2016;13:31---7. 26. Alberts B. Science breakthroughs. Science. 2011;334:1604. 27. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365:493---505. 28. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al. Antiretroviral therapy for the prevention of HIV-1 transmission. N Engl J Med. 2016;375:830---9.
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29. Montaner JS, Lima VD, Barrios R, Yip B, Wood E, Kerr T, et al. Association of highly active antiretroviral therapy coverage, population viral load, and yearly new HIV diagnoses in British Columbia, Canada: a population-based study. Lancet. 2010;376:532---9. 30. Tanser F, Bärnighausen T, Grapsa E, Zaidi J, Newell ML. High coverage of ART associated with decline in risk of HIV acquisition in rural Kwa Zulu-Natal, South Africa. Science. 2013;339:966---71. 31. Rodger AJ, Cambiano V, Bruun T, Vernazza P, Collins S, van Lunzen J, et al. Sexual activity without condoms and risk of HIV transmission in serodifferent couples when the HIVpositive partner is using suppressive antiretroviral therapy. JAMA. 2016;316:171---81. 32. Lima VD, Johnston K, Hogg RS, Levy AR, Harrigan PR, Anema A, et al. Expanded access to highly active antiretroviral therapy: a potentially powerful strategy to curb the growth of the HIV epidemic. J Infect Dis. 2008;198:59---67. 33. Granich RM, Gilks CF, Dye C, de Cock KM, Williams BG. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet. 2009;373:48---57. 34. McCormack S, Dunn DT, Desai M, Dolling DI, Gafos M, Gilson R, et al. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial. Lancet. 2016;387:53---60. 35. Molina JM, Capitant C, Spire B, Pialoux G, Cotte L, Charreau I, et al. On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. N Engl J Med. 2015;373:223---46. 36. Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367: 399---410. 37. Thigpen MC, Kebaabetswe PM, Paxton LA, Smith DK, Rose CE, Segolodi TM, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367:423---34. 38. Nel A, van Niekerk N, Kapiga S, Bekker LG, Gama C, Gill K, et al. Safety and efficacy of a dapivirine vaginal ring for HIV prevention in women. N Engl J Med. 2016;375:2133---43. 39. Baeten JM, Palanee-Phillips T, Brown ER, Schwartz K, SotoTorres LE, Govender V, et al. Use of a vaginal ring containing dapivirine for HIV-1 prevention in women. N Engl J Med. 2016;375:2121---32. 40. Grant RM, Anderson PL, McMahan V, Liu A, Amico KR, Mehrotra M, et al. Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: a cohort study. Lancet Infect Dis. 2014;14: 820---9. 41. Liu AY, Cohen SE, Vittinghoff E, Anderson PL, Doblecki-Lewis S, Bacon O, et al. Preexposure prophylaxis for HIV infection integrated with municipal- and community-based sexual health services. JAMA Intern Med. 2016;176:75---84. 42. Volk JE, Marcus JL, Phengrasamy T, Blechinger D, Nguyen DP, Follansbee S, et al. No new HIV infections with increasing use of HIV preexposure prophylaxis in a clinical practice setting. Clin Infect Dis. 2015;61:1601---3.
ARTICLE IN PRESS
Rev Clin Esp. 2017;xxx(xx):xxx---xxx
Revista Clínica Española www.elsevier.es/rce
SPECIAL ARTICLE
HIV/AIDS infection: The beginning of the end for today’s greatest pandemic?夽 F. Gutiérrez Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital General Universitario de Elche, Universidad Miguel Hernández, Alicante, Spain Received 2 February 2017; accepted 18 April 2017
KEYWORDS HIV; AIDS epidemic; Antiretroviral therapy; HIV eradication; HIV cure
PALABRAS CLAVE VIH; Epidemia de sida; Terapia antirretroviral; Erradicación del VIH; Curación del VIH
Abstract Recently, there have been significant advances in the fight against human immunodeficiency virus, which have increased the hopes of definitively halting its dissemination and of starting the decline of the epidemic it has caused. Transmission of the infection was drastically reduced when infected patients were given antiretroviral treatments, which boosted the diffusion of treatments to middle- and low-income countries. Global therapy coverage has doubled in recent years; meanwhile the incidence of new infections has decreased. Various curative strategies are also actively being investigated, including those aiming to induce cell resistance to the infection through gene therapy and the elimination of latent virus reservoirs. This article reviews the current situation and future developments in terms of controlling the pandemic and, eventually, curing the infection. © 2017 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.
Infección por el VIH/sida: ¿El principio del fin de la primera gran pandemia contemporánea? Resumen En los últimos a˜ nos se han producido avances importantes en la lucha contra el virus de la inmunodeficiencia humana que hacen concebir esperanzas de que pueda detenerse definitivamente su diseminación y de que la epidemia que ha provocado entre en fase de declive. Se ha demostrado que el tratamiento antirretroviral de los pacientes infectados reduce drásticamente la transmisión de la infección, lo que ha impulsado la extensión de los tratamientos a los países de renta media y baja. La cobertura terapéutica a escala mundial se ha duplicado
夽 Please cite this article as: Gutiérrez F. Infección por el VIH/sida: ¿El principio del fin de la primera gran pandemia contemporánea? Rev Clin Esp. 2017. http://dx.doi.org/10.1016/j.rce.2017.04.004 E-mail address: gutierrez [email protected]
2254-8874/© 2017 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.
RCENG-1400; No. of Pages 5
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ARTICLE IN PRESS
2
F. Gutiérrez en los últimos a˜ nos y de forma paralela se ha reducido la incidencia de nuevas infecciones. Al mismo tiempo se están investigando activamente diferentes estrategias para la curación, entre ellas las encaminadas a inducir resistencia celular a la infección mediante terapia génica y la eliminación de los reservorios de virus latente. En este artículo se revisa la situación actual y las perspectivas futuras para controlar la pandemia y, quizá, curar la infección. © 2017 Elsevier Espa˜ na, S.L.U. y Sociedad Espa˜ nola de Medicina Interna (SEMI). Todos los derechos reservados.
Background The acquired immune deficiency syndrome (AIDS) pandemic is undoubtedly the most significant of modern times. Of all known viruses, the human immunodeficiency virus (HIV) has one of the highest lethality rates. Since its onset in 1981, HIV has caused the death of more than 30 million individuals. The most recent estimates by the World Health Organization (WHO) and the Joint United Nations Program on HIV and AIDS (UNAIDS) indicate that 37 million individuals are currently infected.1 Each year, 2 million new infections are produced, and more than 1 million individuals die from the disease worldwide. In the 35 years of struggle against AIDS, there have been major scientific advances that have been transferred in an exemplary fashion to real life. These advances have helped convert HIV infection into a controllable chronic disease. An important scientific milestone was the identification of HIV in 1983, only 2 years after declaring the first cases of AIDS in the US. Shortly thereafter, the virus’ genetic organization was discovered. Studies showed that the main targets of HIV were the T lymphocytes and that the most important cell receptor was the RCA-4 (CD4) protein, although the entry of the virus into the cells also required the binding to other proteins of the cell membrane, called coreceptors, whose natural ligands are different chemokines. The 2 main coreceptors of HIV are CCR5 and CXCR4, and most new infections are caused by viruses that use CCR5 to enter the cells (virus with R5 tropism).2 We know that activated T-CD4(+) lymphocytes are often infected, which is where transcription of the HIV genome is started. Within a few hours, massive viral replication occurs, with destruction of the infected cells.3 Over time, the progressive cell destruction leads to T-CD4(+) lymphopenia, with damage to the architecture of the lymph nodes and other lymphoid tissues, as well as immunoactivation and general dysregulation of the immune function. In a median of approximately 10 years, the patient develops severe immunodeficiency.3 There is, however, considerable heterogeneity in the outcomes of patients with the infection, ranging from rapid progression to the so-called elite controllers, a rare group of individuals who for years maintain spontaneous control over viral replication without treatment.4 Variants have also been described in the human genome that confer natural resistance to infection by this virus. The best characterized of these variants is a deletion of a gene segment of coreceptor CCR5 (CCR5-32), which
impedes penetration by the virus with tropism R5 in the lymphocytes.5 Individuals with this homozygous CCR5-32 variant (less than 1% of the white population) are highly resistant to HIV infection, even after repeated exposure to the virus.6
Achievements and limitations of antiretroviral therapy In the last 2 decades, increasingly effective antiretroviral drugs have been developed, and a continuous reduction in overall mortality for AIDS has been documented.7 The current antiretroviral therapy (ART) regimens can achieve virological suppression (defined by the inability to detect viruses in the blood using highly sensitive molecular techniques) in almost 90% of cases,8 which has translated in a growing proportion of patients who are virologically controlled. Thanks to the widespread use of prophylaxis with antiretrovirals during pregnancy, the vertical transmission of the infection has been practically eliminated in high-income countries.9 Since the first decade of the 21th century, international initiatives have been launched with public and private funds that, aligned with the WHO directives, have implemented ART programs in low to middle-income countries. Thus, in 2009, more than 30% of infected patients in Africa had access to treatment. Following an incessant increase in worldwide mortality from AIDS that exceeded 2.5 million deaths annually, since 2005, there has been a documented reduction in mortality from this cause, which continues to this day.1 The achievements of ART have undoubtedly been significant. However, long-term administration of antiretroviral drugs also has many disadvantages10---13 and does not eradicate the infection. Patients who are kept in a state of virological suppression with ART are known to have proviral DNA with replicative capacity. It has been shown that discontinuing ART in these patients is inevitably followed by a rebound in viremia due to the presence of cellular reservoirs of the virus.14 These reservoirs are rapidly established after the infection and mainly consist of lymphocytes infected with already integrated virus that enter a state of rest/latency.15 These lymphocytes with latent infection and without detectable replication represent a small proportion of the total infected lymphocytes (less than one per million) but have a long half-life (months-years). These cells do not express any viral marker or protein on their surface and are
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HIV/AIDS infection: The beginning of the end for today’s greatest pandemic? therefore not recognized by the immune system. Due to the absence of replication, these cells are also ‘‘invisible’’ to antiretroviral drugs.16 ART thereby prevents the progression but does not cure the infection.
The first steps toward a cure In 2009, news broke on what is currently the only documented case of a patient being cured of HIV: the so-called ‘‘Berlin patient’’.17 This patient was infected by HIV and developed acute myeloblastic leukemia. The patient underwent intensive chemotherapy to cure the leukemia and received a hematopoietic stem cell transplant from a donor homozygous for the CCR5-32 deletion. Before the transplantation, the ART was interrupted. The surprise was that, following transplantation, the patient continued to maintain undetectable plasma viral loads without ART. Although the HIV was exhaustively sought in the blood and tissues, there was no trace of the virus 10 years later. This case represents a proof of concept that an ablative hematologic therapy followed by transplantation with HIV-resistant cells could cure the infection. Unfortunately, bone marrow transplantation is a complex and costly procedure, which also requires the concomitant use of immunosuppressants that can cause adverse effects, including a greater risk of opportunistic infections, and it is therefore not a viable strategy for the general treatment of patients infected by HIV. Moreover, finding donors that are homozygous for CCR5-32 is difficult, because this genetic variant is present in less than 1% of the white population.6 The experience of the ‘‘Berlin patient’’ has opened the door to curative strategies based on gene therapy. One of the most promising initiatives is based on the possibility of obtaining HIV-resistant CD4+ lymphocytes in the laboratory using genetic engineering techniques. To this end, zinc finger nucleases (ZFN) designed to modify the gene of coreceptor CCR-5 are employed, deleting the 32 base pairs missing in the CCR5-32 deletion. Tebas et al. assessed the results of a clinical trial that infused these genetically modified CD4+ lymphocytes into patients with chronic HIV infection and good virologic control with ART.18 The procedure consisted of extracting lymphocytes from the patients using apheresis, which were then genetically modified in the laboratory and reinfused into the patients. After reinfusion, a significant increase in the number of circulating CD4+ lymphocytes and genetically modified CD4+ lymphocytes was observed. Subsequently, a subgroup of these patients had their ART suspended with the intent to allow the HIV to replicate. The study observed that the genetically modified lymphocytes survived better against the virus replication.18 The study’s positive results raise hopes about the future of gene therapy with this and other strategies aimed at inducing cell resistance to the infection through the elimination of genes that encode the coreceptor CCR5 and other key proteins in the entry process, such as the fusion peptide, a fundamental structure for producing the fusion between the HIV membranes and the target cell.19 Another of the strategies undergoing research for curing HIV is the so-called ‘‘shock and kill’’, which seeks to eliminate the viral reservoirs by activating and destroying the resting lymphocytes that contain integrated virus. There
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are several compounds that can reactivate the infected cells in a latent manner and induce the production of viral proteins. These compounds include histone deacetylase (HDAC) inhibitors, such as vorinostat, romidepsin and panobinostat.20,21 HDACs directly regulate the mechanism of HIV latency, inducing histone deacetylation in the virus integration sites. Histone acetylation translates into a transcription activation. Although the mechanism by which the HDAC inhibitors induce HIV reactivation in the resting lymphocytes is not entirely known, the inhibitors are believed to activate the HIV promoter sequence, inducing nucleosome hyperacetylation of the promoter sequence and suppressing the binding of HDACs to the HIV promoter sequence. The antilatency drugs studied so far have individually had a modest effect on the latent cellular reservoir. It is currently believed that a combination of 2 or more latencyreversing agents might be necessary to reduce the cellular reservoir and that it might also be necessary to boost the immune system so that it more effectively recognizes the infected cells and destroys them. This immune potentiation could hypothetically be conducted by ‘‘spurring’’ the cytotoxic lymphocytes to delete the reservoir cells where the HIV is reactivated, through therapeutic vaccines22 or with neutralizing antibodies. The use of broad spectrum neutralizing antibodies against viral proteins to clear viruses that are replicating and infected cells is one of the strategies that has raised the most expectations in recent years.23---25
Treatment as prevention: the hope for controlling the pandemic Pending new scientific milestones that accelerate the cure of the infection, relevant progress has taken place in recent years in epidemiological and clinical research, which have raised hopes about controlling the pandemic. One of these advances has been recognizing that ART is a powerful preventive tool, a finding that was considered the 2011 scientific breakthrough of the year by the journal Science.26 Before 2011, observational studies had been published on couples who were serodifferent for HIV (one member of the couple was infected and the other not), which indicated that HIV transmission was less likely if the infected partner was undergoing ART. The HIV Prevention Trials Network 052 study included 1763 serodifferent couples, mostly heterosexual, with a T-CD4 lymphocyte count in peripheral blood of 350---550 cells/L.27 The couples were randomized to 2 arms: immediate or deferred ART of the index case. In the latter case, therapy was postponed until the T-CD4 lymphocyte count dropped below 250 cells/L. The patients who began ART immediately had a 96% lower risk of transmitting the infection to their partner. In the deferred therapy arm, 27 individuals were infected in the deferred therapy group and only 1 was infected in the immediate therapy group.27 After determining these results, all infected patients who participated in the trial were offered ART (index cases). The study included follow-up of the couples for more than 5 years to assess the duration of the ART effect in preventing transmission. The efficacy lasted over time, and in fact there were no documented phylogenetically related transmissions when the index case maintained a stable undetectable HIV plasma viral load with ART.28
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4 Population studies have confirmed that increasing the number of treated individuals in a certain population can reduce HIV transmissions.29,30 In British Columbia (Canada), it was observed that as the populational viral load decreased (as a result of an increase in the number of infected patients with suppressed viral load, as a reflection of better antiretroviral coverage of the population), the number of new diagnoses of HIV infection also decreased.29 Similar results have also been observed in studies in Africa. A study in KwaZulu-Natal (South Africa) showed that high therapeutic coverage in the population with HIV infection in a specific geographical area was closely associated with the incidence of new infections in this area.30 The efficacy of ART in preventing HIV transmission has also been confirmed in a European study with hundreds of serodifferent couples.31 These results have led many experts in recent years to propose the strategy known as ‘‘Universal Test and Treat’’; in other words, performing the HIV infection detection test for the entire population and treating all those with the infection. This proposal is based on the fact that if we consider the scientific evidence that ART drastically reduces the risk of transmission, the more individuals who are treated, the less circulating virus there will be in the population and thus fewer infections. Various mathematical models have determined that universal voluntary screening for HIV, followed by immediate ART for detected cases, would be an effective strategy for eliminating HIV transmission, which would speed the transition from the current endemic phase to an elimination phase.32,33 Recognition of the efficacy of ART as a preventive tool has prompted its availability in low to middle-income countries. From 2010 to 2015, the therapeutic coverage doubled, from 23% to 46% of infected individuals worldwide.1 In its latest report, UNAIDS disseminated optimistic data on the evolution of the pandemic. In recent years, new infections in children have decreased 50%, and overall mortality has been reduced by more than 45%. These reductions have coincided with a considerable increase in access to ART, from 7.5 million individuals in 2010 to more than 18 million in 2015.1 With the goal of definitively stopping and reversing the spread of HIV and accelerating the epidemic’s decline, ambitious objectives have been set for 2020: diagnose 90% of those infected, treat 90% of those diagnosed and achieve stable undetectable HIV plasma viral loads in 90% of those treated.
Future prospects To control the AIDS pandemic, the scientific advances in the field of treatment for infected patients should be supplemented with research into new preventive strategies and the widespread use of those strategies whose efficacy has been well documented, such as the use of barrier methods. One of the areas of greatest interest in recent years has been pre-exposure prophylaxis with antiretroviral drugs in individuals with a high risk of infection through sexual relations.34---39 Studies performed to date have shown that pre-exposure prophylaxis in heterosexual men and women is safe and reduces the transmission of the infection, although the results have been mixed, depending on treatment adherence.36---39 Recently published results from 2 large clin-
F. Gutiérrez ical trials conducted with men who had sexual relations with men showed that pre-exposure prophylaxis lowered the risk of infection by 86%.34,35 The efficacy of pre-exposure prophylaxis has been confirmed in observational studies after implementing specific programs in various settings,40---42 and its predicted extension could be an additional strategy that significantly contributes to controlling the pandemic. The WHO predictions indicate that if the 90---90---90 objectives are achieved by 2020, the trend of the HIV/AIDS epidemic could be reversed. A 70% reduction is estimated in the incidence rate of new infections between 2010 and 2030, as well as a 65% reduction in mortality, which could be less than 500,000 deaths annually in 2030. Although the expectations of gaining control over the pandemic in the coming decades are high, we should recognize that there is still time to achieve the desired objectives: understanding how to cure the infection and definitively eradicating it. Although some curative strategies mentioned earlier are already being evaluated in clinical trials, it is expected that it will take some time until they can be applied in clinical practice. Meanwhile, the extension and globalization of preventive strategies, early diagnosis and current treatment could bring us steadily closer to the goal of ending one of the most significant contemporary pandemics.
Conflict of interests The author declares that he has no conflicts of interest.
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