Contents

An outbreak evolves—changes to an epidemic and to treatment

An important note

In this issue of TreatmentUpdate we describe and detail important changes that have shifted scientific understanding about the effect of HIV on the immune system, and the need for early treatment of HIV. We also explore some issues related to undiagnosed HIV infection and why some people may be reluctant to initiate therapy for HIV.

To help readers better understand the origin of the emotional legacy that can stick to HIV to this day, it is necessary to revisit the early years of the HIV pandemic. Some of the issues that we mention may be disturbing for some readers, particularly for those who have lived through those early years. However, by unpacking the issues of that era, we show later how these issues can continue to affect decisions about testing and initiation of treatment for some people in the current era.

Looking back in time

In the 1960s and mid-to-late 1970s, doctors in North America, Western Europe and Central Africa began to see rare cases of severe and worsening immune deficiency in previously healthy, generally young adults. As such cases were rare in that era and did not seem to be connected, doctors were deeply puzzled and made no progress in finding the cause of the unexplained syndrome that bedevilled their patients.

Searching backwards

Commenting on the probable origins of HIV in the early 1980s, Professor Ib Bygbjerg, MD, of the University of Copenhagen, who documented a case of AIDS that occurred in the late 1970s, stated: “Three acutely deadly viruses of central African origin have been discovered in recent years (Lassa, Marburg and Ebola).” Therefore, it is not surprising that another virus that caused serious illness would have originated there.

Over the next 35 years, by closely reexamining medical records on early cases and, when possible, testing stored blood and tissue samples for HIV antibodies and HIV itself, and analysing the genes carried by different strains of HIV, researchers were partially able to trace the early trajectory of this virus out of Africa.

But interest in finding the origins of AIDS likely would have been delayed had cases of AIDS and its precursor conditions not so suddenly and spectacularly begun to appear in simultaneous clusters among largely middle-class gay and bisexual young men in New York, Los Angeles, San Francisco and the cities of Western Europe in the early 1980s. At the same time, cases among heterosexual people were also occurring in Central Africa, though initially this was hardly noticed in the West.

Researchers were subsequently able to find a virus that was closely related to HIV, called simian immunodeficiency virus (SIV), in many species of monkeys and apes in parts of sub-Saharan Africa. Exactly how and when people became infected with SIV and when this virus mutated into HIV remains unclear.

Such spillover of a virus from one species to another likely happened many times over thousands of years. So why didn’t an AIDS epidemic occur in the past? Perhaps something was different in the early and mid-20th century. Some evidence suggests the possibility that large-scale reuse of syringes and needles as part of public health programs in the early and mid-20th century in colonial parts of central Africa may have played a role in igniting the AIDS epidemic. Add urbanization, social changes and faster transportation routes (including air travel)—HIV would have begun to spread outside of central Africa by the 1960s.

Studies into the origins of HIV, particularly the closely related virus SIV found in monkeys, are important. Understanding how some monkeys have developed the ability to resist SIV infection may one day yield clues for creating an effective HIV vaccine or assist efforts to find a cure for HIV.

The shock of the new

When the syndrome that would later be called AIDS first appeared in high-income countries in the early 1980s, news of its arrival was greeted with surprise, shock and fear.

Now, in the fourth decade of the HIV pandemic, it may be hard for some people to understand the emotions that arose very early in its history.

However, at the dawn of the pandemic there were many mysteries. The chief one being, why were apparently healthy young men suddenly succumbing to unusual life-threatening infections and rare cancers? Scientists did not know which germ caused the new syndrome, exactly how it spread or why it wreaked such havoc with the immune system. News media of the day carried stories not always based on firm evidence, fueling fear, panic and hysteria. The syndrome was also associated with generally despised and persecuted minorities—men who had sex with men and people with addictions who injected street drugs. Observers of the early years of AIDS noted that the news about the new syndrome was associated with two powerful emotional issues—sex and death. This affected how some people viewed the syndrome and the larger society’s response to it.

To add to its mystery, once the arrival of AIDS was officially documented in gay men, additional cases began to appear in heterosexual people, babies and recipients of contaminated blood and blood products (such as hemophiliacs). However, despite this broadening of key populations, the syndrome would remain associated with gay men and drug users.

Views from an epidemic

In the early 1980s, psychologists in Los Angeles and San Francisco described what it was like to be at the centre of the emerging AIDS epidemic:

“An unidentified disease mysteriously focuses on one group. This group, of which you are a member, is a minority. Your friends are becoming ill and are dying ugly and painful deaths. Even the ringing of the telephone is no longer a friendly sound: It may be bringing yet more painful news. You watch yourself daily for symptoms. People in the general population are becoming frightened of catching the disease from you. The government shows a curious lethargy in response to what has, within two years, become one of medical history's most enigmatic major epidemics. There is talk of quarantine. This disease has an incubation period that can be as long as three years, and large numbers of your group may have already contracted the dread disease without knowing it. Even the most healthy-looking people may be capable of transmitting the mysterious agent. Everyone is terrified.”

Several years later, commenting in The New York Times on how society had responded to AIDS in 1986, H. Jack Geiger, MD, said:

“…great and lethal epidemics are never merely biological events and never elicit merely biological or scientific responses. They become social forces in their own right, carving deep new fissures in the political and cultural landscape, thrusting up buried fears and hatreds.”

Biomedical progress begins to occur

Due to perseverance and persistence, the cause of AIDS—a virus we now call HIV—was discovered in France in 1983, and the first test to help diagnose HIV infection was made commercially available in 1985. As the numbers of HIV-positive people rose quickly, along with documented deaths, pharmaceutical companies began to develop potential treatments.

Early forms of treatment

By today’s standards, anti-HIV drugs that were tested in the mid-to-late 1980s had limited benefit, in some cases initially had to be given intravenously, and often caused serious side effects. However, by 1996, combinations of powerful anti-HIV agents became available in Canada and other high-income countries. At the time, these combinations were dubbed highly active antiretroviral therapy (HAART). They worked much better than the anti-HIV drugs that came before them, causing near-miraculous recoveries for some people with AIDS. Thanks to HAART, for the first time people with AIDS were able to resist and recover from formerly life-threatening infections, the lesions and tumours associated with a common AIDS-related cancer called Kaposi’s sarcoma (KS) and even some other AIDS-related cancers.

Pills and side effects

HAART was not without issues. The regimens that became available in 1996 and for many years after were cumbersome. People sometimes had to take a handful of pills at least twice, if not three times daily. Some drugs had food and water requirements. Also, drugs in that era could cause a range of short- and long-term side effects, from regular bouts of nausea, vomiting and/or diarrhea to changes in a person’s appearance. This latter issue was distressing for affected patients and caused researchers to engage in more study of side effects and to find safer medicines.

In 2015

Fast-forward to the present. Potent combination anti-HIV therapy is no longer called HAART but simply ART. More importantly, the combinations recommended for the initial treatment of HIV are much safer—and simpler—than many treatments that were used in the past. For example, regimens recommended for the initial therapy of HIV today by the U.S. Department of Health and Human Services have not been found to cause changes in body shape. And entire combinations are available in just one pill that needs only be taken, in many cases, once daily.

The power of ART is so profound that researchers in Canada, Australia, the U.S. and Western Europe predict that the life expectancy of some HIV-positive people will be near normal. They estimate that a young adult who is infected today and diagnosed shortly thereafter, and who quickly begins ART and is able to take it exactly as directed every day, and who responds well to treatment, and who does not have other pre-existing health-related issues (serious co-infections, addictions and so on) should be able to live into their 70s or even 80s. This optimistic forecast is based on trends seen in tens of thousands of HIV-positive people who are being monitored in many high-income countries. It is a far cry from the fate of HIV-positive people upon diagnosis in the 1980s and early 1990s.

A prevention plus

ART’s impact on HIV also has tremendous benefits for people who do not have this virus. By reducing the amount of HIV in the blood to very low levels, ART can allow HIV-positive mothers to give birth to healthy, uninfected babies. The effect of ART on HIV also significantly reduces the risk of HIV being spread through sex. This latter effect is encouraging policy planners to increase the availability of ART in some regions so that the spread of HIV can greatly be reduced.

The power of history, emotions and stigma

Despite all the good news summarized here, HIV and its treatment, to varying degrees, are still dogged by complex historical and deep emotional issues for some people. These issues may affect a person's ability to accept that they may be at risk for acquiring HIV and their willingness to get tested and may also underpin a reluctance to initiate ART.

The historical and emotional legacy that often sticks to HIV today can be so powerful and causes such distress that some people, dubbed "denialists" by psychologists, still seek to deny the existence of HIV. It is striking that other viruses and their associated diseases—polio, smallpox, measles, hepatitis B and C, rabies, SARS and the flu—have not drawn such a particularly heated emotional response.

The intersection of biomedical treatment and prevention

In the nearly 35 years since AIDS was first officially noticed, the cause of this syndrome, HIV, has spread around the world. It is not likely that there will be a highly effective vaccine in the next 10 years. So efforts to help slow the spread of HIV at the level of a city, region or country will likely focus on accelerating access to HIV testing to help uncover previously undiagnosed infections, followed by counselling and the swift offer of treatment. Furthermore, health systems will likely pay more attention to ART users to help ensure that they are able to take ART every day and achieve a low viral load. In some cities and regions, HIV pre-exposure prophylaxis (PrEP) may also become more available in the years ahead.

In this issue of TreatmentUpdate, we provide details about important changes to treatment arising from recent clinical trials. We also explore some issues related to care and treatment—such as the cascade of care, uncovering undiagnosed HIV and why some people may be reluctant to initiate ART.

—Sean R. Hosein

REFERENCES:

  1. Faria NR, Rambaut A, Suchard MA, et al. HIV epidemiology. The early spread and epidemic ignition of HIV-1 in human populations. Science. 2014 Oct 3;346(6205):56-61.
  2. Pépin J. The expansion of HIV-1 in colonial Leopoldville, 1950s: driven by STDs or STD control? Sexually Transmitted Infections. 2012 Jun;88(4):307-12.
  3. Worobey M, Gemmel M, Teuwen DE, et al. Direct evidence of extensive diversity of HIV-1 in Kinshasa by 1960. Nature. 2008 Oct 2;455(7213):661-4.
  4. Zhu T, Korber BT, Nahmias AJ, et al. An African HIV-1 sequence from 1959 and implications for the origin of the epidemic. Nature. 1998 Feb 5;391(6667):594-7.
  5. Gilbert MT, Rambaut A, Wlasiuk G, et al. The emergence of HIV/AIDS in the Americas and beyond. Proceedings of the National Academy of Sciences USA. 2007 Nov 20;104(47):18566-70.
  6. McCarthy KR, Kirmaier A, Autissier P, et al. Evolutionary and functional analysis of old world primate TRIM5 reveals the ancient emergence of primate lentiviruses and convergent evolution targeting a conserved capsid interface. PLoS Pathogens. 2015; 11(8): e1005085.
  7. Nemeth A, Bygdeman S, Sandström E, et al. Early case of acquired immunodeficiency syndrome in a child from Zaire. Sexually Transmitted Diseases. 1986 Apr-Jun;13(2):111-3.
  8. Nzilambi N, De Cock KM, Forthal DN, et al. The prevalence of infection with human immunodeficiency virus over a 10-year period in rural Zaire. New England Journal of Medicine. 1988 Feb 4;318(5):276-9.
  9. Sterry W, Marmor M, Konrads A, et al. Kaposi's sarcoma, aplastic pancytopenia, and multiple infections in a homosexual. Lancet. 1983 Apr 23;1(8330):924-5.
  10. Frøland SS, Jenum P, Lindboe CF, et al. HIV-1 infection in Norwegian family before 1970. Lancet. 1988 Jun 11;1(8598):1344-5.
  11. Bygbjerg IC. AIDS in a Danish surgeon (Zaire, 1976). Lancet. 1983 Apr 23;1(8330):925.
  12. Jonassen TO, Stene-Johansen K, Berg ES, et al. Sequence analysis of HIV-1 group O from Norwegian patients infected in the 1960s. Virology. 1997 Apr 28;231(1):43-7.
  13. Garry RF, Witte MH, Gottlieb AA, et al. Documentation of an AIDS virus infection in the United States in 1968. Journal of the American Medical Association. 1988 Oct 14;260(14):2085-7.
  14. Rogan E Jr, Jewell LD, Mielke BW, et al. A case of acquired immune deficiency syndrome before 1980. CMAJ. 1987 Oct 1;137(7):637-8.
  15. Saimot AG, Coulaud JP, Mechali D, et al. HIV-2/LAV-2 in Portuguese man with AIDS (Paris, 1978) who had served in Angola in 1968-74. Lancet. 1987 Mar 21;1(8534):688.
  16. Getchell JP, Hicks DR, Svinivasan A, et al. Human immunodeficiency virus isolated from a serum sample collected in 1976 in Central Africa. Journal of Infectious Diseases. 1987 Nov;156(5):833-7.
  17. Sonnet J, Michaux JL, Zech F, et al. Early AIDS cases originating from Zaïre and Burundi (1962-1976). Scandinavian Journal of Infectious Diseases. 1987;19(5):511-7.
  18. Vandepitte J, Verwilghen R, Zachee P. AIDS and cryptococcosis (Zaire, 1977). Lancet. 1983 Apr 23;1(8330):925-6.
  19. Selik RM, Haverkos HW, Curran JW. Acquired immune deficiency syndrome (AIDS) trends in the United States, 1978-1982. American Journal of Medicine. 1984 Mar;76(3):493-500.
  20. Huminer D, Rosenfeld JB and Pitlik SD. AIDS in the pre-AIDS era. Reviews of Infectious Diseases. 1987 Nov-Dec;9(6):1102-8.
  21. Noel GE. Another case of AIDS in the pre-AIDS era. Reviews of Infectious Diseases. 1988 May-Jun;10(3):668-9.
  22. Jaffe HW, Bregman DJ, Selik RM. Acquired immune deficiency syndrome in the United States: the first 1,000 cases. Journal of Infectious Diseases. 1983 Aug;148(2):339-45.
  23. Altman LK. Rare cancer seen in 41 homosexuals. The New York Times. 3 July 1981. Available at: http://tinyurl.com/lvpujeu [subscription may be required].
  24. Centers for Disease Control (CDC). Pneumocystis pneumonia—Los Angeles. MMWR Morb Mortal Wkly Rep. 1981 June 5;30(21):250-252.
  25. Centers for Disease Control (CDC). Kaposi’s sarcoma and Pneumocystis pneumonia among homosexual men—New York City and California. MMWR Morb Mortal Wkly Rep. 1981 Jul 3;30(25):305-8.
  26. Gottlieb GJ, Ragaz A, Vogel JV, et al. A preliminary communication on extensively disseminated Kaposi’s sarcoma in young homosexual men. American Journal of Dermapathology. 1981 Summer;3(2):111-4.
  27. Gerstoft J, Malchow-Møller A, Bygbjerg I, et al. Severe acquired immunodeficiency in European homosexual men. British Medical Journal. 1982 Jul 3;285(6334):17-9.
  28. Barré-Sinoussi F, Chermann JC, Rey F, et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science. 1983 May 20;220(4599):868-71.
  29. Altman LK. New homosexual disorder worries health officials. The New York Times. 11 May 1982. Available at: http://tinyurl.com/pnsulet [subscription may be required].
  30. Henig RM. AIDS—A new disease’s deadly odyssey. The New York Times Magazine. 3 February 1983. Available at: http://tinyurl.com/ouygglu [subscription may be required].
  31. Norman M. Homosexuals confronting a time of change. The New York Times. 16 June 1983. Available at: http://tinyurl.com/ptr2n8o [subscription may be required].
  32. Anonymous. The fear of AIDS. The New York Times. 25 June 1983. Available at: http://tinyurl.com/p7zcxcx [subscription may be required].
  33. Glass RM. AIDS and suicide. JAMA. 1988 Mar 4;259(9):1369-70.
  34. Morin SF, Charles KA, Malyon AK. The psychological impact of AIDS on gay men. American Psychologist. 1984 Nov;39(11):1288-93.
  35. Geiger HJ. Plenty of blame to go around. The New York Times. 8 November 1987. Available at: http://www.nytimes.com/1987/11/08/books/plenty-of-blame-to-go-around.html [subscription may be required].
  36. Yarchoan R, Klecker RW, Weinhold KJ, et al. Administration of 3'-azido-3'-deoxythymidine, an inhibitor of HTLV-III/LAV replication, to patients with AIDS or AIDS-related complex. Lancet. 1986 Mar 15;1(8481):575-80.
  37. de Waal R, Cohen K, Maartens G. Systematic review of antiretroviral-associated lipodystrophy: lipoatrophy, but not central fat gain, is an antiretroviral adverse drug reaction. PLoS One. 2013 May 28;8(5):e63623.
  38. Lohse N, Hansen AB, Gerstoft J, et al. Improved survival in HIV-infected persons: consequences and perspectives. Journal of Antimicrobial Chemotherapy. 2007 Sep;60(3):461-3.
  39. May MT, Gompels M, Delpech V, et al. Impact on life expectancy of HIV-1 positive individuals of CD4+ cell count and viral load response to antiretroviral therapy. AIDS. 2014 May 15;28(8):1193-202.
  40. Samji H, Cescon A, Hogg RS, et al. Closing the Gap: Increases in life expectancy among treated HIV-positive individuals in the United States and Canada. PLoS One. 2013 Dec 18;8(12):e81355.
  41. Lewden C, Chene G, Morlat P, et al. HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. Journal of Acquired Immune Deficiency Syndromes. 2007 Sep 1;46(1):72-7.
  42.  Smith TC. Interview with HIV denier-turned-science-advocate John Strangis. Aetiology. 20th August, 2015. Available at: http://scienceblogs.com/aetiology/2015/08/20/interview-with-hiv-denier-turned-science-advocate-john-strangis/
  43. Gallo RC. Developing a successful HIV Vaccine. Journal of Infectious Diseases. 2015 Jul 15;212 Suppl 1:S40-1.