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Defining some terms
(These are not 100 percent accurate “text book” definitions but they will suffice for the purposes of this article)
Reinfection getting reinfected with an organism that the body has previously been infected with and where it has cleared the previous infection.
HIV Superinfection a second infection with a second and different “type” of HIV after an individual has developed an immune response to the initial “type” of HIV (the terms reinfection and superinfection are often used interchangeably in HIV).
HIV co-infection being initially infected with two different “types” of HIV at the same time.
Recombinant HIV a form of HIV that is a “hybrid” of two different types. Such recombinant forms can only occur if at some point the body was infected with two different types of HIV.
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HIV Australia Vol. 3 No. 4 - Features
June - August 2004
Superinfection - A Changing Picture
By Ross Duffin
When gay men were defining the safe-sex culture in response to crisis, the initial rules were the same for all. Regardless of whether you were HIV-positive or negative, it was safe sex always and ‘assume everybody is positive’. The well-meaning intent was to avoid sexual ‘ghettoisation’ based on serostatus.
It didn’t take long for gay men to work out that if both partners were HIV-negative and in a committed relationship or both were HIV-positive, then maybe ‘safe sex always’ did not apply. The question for HIV-positive men was whether reinfection (or superinfection) with another strain of HIV could happen, and if it did happen, whether it had any significance on disease progression.
For people with HIV, superinfection is a concern because they may get super-infected with a more virulent (“nasty”) type of HIV, or HIV that is resistant to one or more of the drugs used to treat it. (Although resistant viruses tend to be less virulent and there are two case reports of people who already had resistant viruses being super-infected with virus of wild type – i.e. not resistant – to the detriment of their health and the ability of their bodies to control their HIV infection).
In the late 1980s, I was one of the authors of an ad that said yes, superinfection could happen, and yes it might have significance. The major motivation for the ad was to reinforce the emergent rules of the safe-sex culture. By the early 1990s, however, consensus had shifted. It was thought that superinfection was a rare event – and if it did happen it didn’t have a lot of significance.
Then effective treatments arrived and it was soon clear that resistance was a potential issue unless dosing schedules were followed properly. There was legitimate concern about resistant strains and the transmission of resistant strains and there became a new reason to find out if superinfection occurred. The jury remained out. Next came the first case report of a confirmed case of superinfection and then more and more. Over time, a new picture has emerged.
Data on the first five confirmed case reports of HIV superinfection
Case 1:2 Involved a 38-year-old man who was diagnosed with acute HIV infection in November 1998. He went on antiviral therapy that was interrupted in January 2001. He had an initial viral rebound to 80,000 copies that then declined to 21,000 copies. He then had a “second rebound” in April 2001 to between 200,000 and 400,000 copies. A detailed analysis of samples revealed he was originally infected with virus of subtype AE and subsequently infected with subtype B during a holiday in Brazil.
Case 2:3 Was presented at the 14th International AIDS Conference in Barcelona in 2002. This person, originally infected with HIV subtype B, was in a treatment interruptions study and had achieved virological control after three interruptions when viral breakthrough occurred. Detailed investigation revealed that the man was reinfected with a different virus of subtype B that was only 12 percent different to the original virus. Despite this, the man was unable to control the second infection.
Cases 3 and 4:4 Involve two injecting drug users (IDUs) from Thailand who were participants in a cohort study. The superinfections were detected from analysing stored samples. Case 3 involves a 30-year-old Thai woman who was initially HIV-negative in June 1996, then HIV-positive to subtype AE in December 1996 and then was identified with subtype B in January 1997. Case 4 involved a 32-year-old Thai male who was initially infected with subtype B and then super-infected with subtype AE seven months after seroconversion.
Case 5:5 Involves a person who was initially infected with drug-resistant HIV of subtype B. They achieved a viral load set point of 6,000 after primary infection. Then in month four, the viral load jumped to 34,000 and then subsequently to 200,000. Detailed investigation revealed they had been superinfected with HIV of subtype B that was wild-type virus (that is not drug resistant). The person was much less able to control the superinfection. (It’s worth noting that in this case superinfection with non-resistant virus had negative implications for HIV progression. This particular drug resistant virus may be harder to treat – but it is less “virulent” or than the wild-type virus).
The case reports mostly relate to people with recent primary infection. None of the superinfections occurred while people were currently on treatments and none involved superinfection with resistant strains (but this does not mean this cannot occur).
From these five reports we can conclude that superinfection does occur but we do not know how often it occurs; that superinfection occurs both within the same subtype (clade) and between different subtypes (which has implications for HIV vaccine development) and that when superinfection occurs it may have big implications for the person’s health and for HIV disease progression.
It needs to be noted that demonstrating superinfection requires very sophisticated methodologies, some of which have only been recently developed and are only available in highly resourced research laboratories. Further, the over representation of acutely infected patients in the case reports may be an artefact because identification of superinfection may be easier in people with robust immune systems and there have been more people with recent primary infection that have been part of intensely monitored cohorts that are likely to lead to the identification of superinfection.
Superinfection Case Report Summary Source: Treatments Roadshow Powerpoint, ATPA
| Case |
Timing Months |
Clade |
Immune response |
| 1 |
30 |
AE/B |
- |
| 2 |
|
B/B |
Strong |
| _ |
3/11 |
AE/B B/AE |
Present only to initial strain |
| 4 |
4 |
B/B R/WT |
- |
No superinfected patient was on HAART
How often does superinfection occur?
Some of the studies that have attempted to answer the question of how often superinfection occurs include:
A study that followed 15 HIV-positive couples for at least two years with sampling every six months. No evidence of superinfection was found.6 (But no data on rates of unprotected sex was given and if there are protective immunological responses this group may be expected to have them).
A large study of HIV positive people in California that examined the protease and reverse transcriptase sequences over time and looked for changes in the sequences that could be due to superinfection. Over 1,072 person-years of observation found no evidence of superinfection.7 (Once again there is no data on risk behaviour and people in this study were on antiviral therapy).
An African study reported on at the 2nd International AIDS Society Conference in Paris in 2003 examined the frequency of recombinant HIV in 147 commercial sex workers on Burkina Faso over time. They identified the appearance of recombinant forms in four cases over two years that coincided with increases in plasma viremia. Their conclusion was that superinfection was not an “uncommon event” (although this is a high-risk population with multiple exposures so others may conclude from the same data that superinfection is still uncommon).8
Most recently, data presented at the 11th Conference of Retroviruses and Opportunistic Infections in San Francisco held in February 2004 documented HIV superinfection occurring at 5 percent a year in a group of recently infected gay men not on HIV antiviral treatments.1
While these studies don’t tell us exactly how often superinfection occurs, we can say it occurs relatively frequently in people with HIV not on treatments. These case reports show that HIV superinfection can occur with HIV of both a different subtype and with the same subtype (there is a common myth that superinfection only occurs with HIV of a different subtype); and have a significant impact on a person’s health and the ability to control HIV infection with antiviral drugs.
HIV superinfection has only been demonstrated in people who are not on antiviral therapy and there is no evidence that shows superinfection could be the cause of unexplained treatments failure.
Given that HIV superinfection does occur quite frequently (although we don’t know exactly how frequently) and that it can be clinically significant for people with HIV, there is a need to inform people with HIV so that they can take measures to protect themselves and their partners.
So what do we say as HIV educators?
Now that we know that superinfection does occur what priority do we give to this changed information? When it became clear in the late 1980s that oral sex could transmit HIV we didn’t rush out and say ‘use condoms for oral sex’. We knew that this was never going to happen – and we had concerns that overstating the risk of oral sex may undermine motivation to sticking to protected anal sex (and indeed there was social science supporting this contention). It is probably similar concerns that have led to some caution emphasising this changed information – particularly given rises in new infections the motivation for this message right now could be misinterpreted. However, we have a fundamental obligation to provide positive people with this information so that can choose to protect themselves and their positive partners.
Superinfection happens. When it does happen it may have a large impact on an individual’s HIV disease progression and additionally it may have an impact on the ability to treat HIV disease. We do not know exactly how often it happens – but the research suggests quite frequently in people with HIV not on treatments. We can’t pretend the evidence is uncertain any longer.
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References
1. Smith D. et al. “Incidence of HIV Superinfection Following Primary Infection.” 11th CROI, San Francisco, abstract 21, 2004.
2. Jost S. et al. “A patient with HIV-1 superinfection.” New England Journal of Medicine 347(10):731-736, 2002.
3. Altfeld M et al Nature 2002 Nov 28;420:434-9
4. Artur Ramos et al. “Intersubtype HIV-1 Superinfection following seroconversion to primary infection in Two Injection Drug Users.” J Virol 2002; 76(15): 7444-52
5. Koelsch K.K. et al. “Clade B HIV-1 superinfection with wild-type virus after primary infection with drug-resistant clade B virus.” AIDS. 2003 May 2;17(7):F11-6.
6. Chakraborty B. et al. “Evaluating HIV-1 superinfection in cell culture, the SCID-hu Thy/Liv model and HIV-infected individuals with high risk of re-exposure to the virus.” Antitviral Therapy 7: S47, 2002.
7. Gonzales M.J., Delwart E., Rhee S.Y., Tsui R., Zolopa A.E.R., Taylor J., Shafer R.W. “Lack of detectable human immunodeficiency virus type 1 superinfection during 1072 person-years of observation.” J Infect Dis. 2003. Aug 1; 188(3):397-405.
8. Manigart O., Courgnaud V., Sanou et. al. “HIV-1 superinfections in a cohort of commercial sex workers in Burkino Faso as assessed by a novel autologous heteroduplex mobility procedure.” ANRS 1245 study. IAS Conference 2003, Jul 13-16, Abstract 72.
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