A Cure for AIDS?

In a midsummer issue of the Journal of Infectious Diseases, Dr Anthony Fauci¹––who is as close as the United States comes to a tsar of AIDS medicine––describes 7 HIV-infected persons who had received protease inhibitor (PI)-based antiretroviral therapy for an average of 40.4 months (range, 31.1 to 54 months). Treatment was initiated very early: a mean 2.7 months following the onset of symptoms of an acute seroconversion reaction. These patients were monitored with regular leukaphereses, enabling the isolation of large numbers of CD4⁺ T cells and the determination of the fraction carrying latent virus.¹ Viral latency is considered the major impediment to viral eradication or, colloquially, a cure for AIDS.

By plotting HIV infectious units per million resting CD4⁺ T cells versus the duration of antiretroviral therapy, the half-life of the latent T-cell reservoir was estimated to be 4.6 months (range, 1.9 to 8.7 months). Given previous determinations that an HIV-positive person has only about a million such cells,² the projected time for complete elimination of HIV in that compartment was 7.7 years (range, 3.1 to 14.5 years). This is considerably shorter than the estimate of multiple decades in an earlier study, which involved patients whose HIV regimens were initiated later in the course of their disease and whose treatment was of shorter duration.²

Postulating that these T cells may be the main, perhaps only, latent reservoir for HIV and that early destruction of nodal architecture and gut-associated lymphoid tissue by HIV would not be an impediment to eliminating virus and enabling immune reconstitution, Fauci's¹ group went on to recommend a key clinical trial. "A close monitoring of the size of viral reservoirs in patients who initiated antiviral therapy early in infection after successful control of HIV for longer than 8 years and who elect to discontinue therapy will be of considerable value in assessing the feasibility of eradication of HIV," was their conclusion.

In a series of interviews, Fauci expanded on this concept. "The first step is to see how far we can push the envelope," he said, suggesting that even more potent regimens, incorporating the fusion inhibitor enfuvirtide and raltegravir, a member of the newest anti-HIV drug class, the integrase inhibitors, would be used in subsequent viral eradication protocols.³ "If doctors could get HIV-positive people completely off their treatment regimens, it might be worth the risk of the aggressive treatment," Fauci said.³

Sure. But there are multiple, steep impediments to reaching that goal in the real world, even if it were ever to be achieved in a single patient in an unusual scenario: very aggressive treatment begun very early after an acute seroconversion.

In an editorial accompanying the Journal of Infectious Diseases study, Drs Margolis and Archin,⁴ who are themselves actively investigating models for viral eradication based on induction of virus from latent reservoirs, further scrutinized the data. They suggested that in 4 of the 7 patients Fauci's group studied, the decay in latent reservoirs may not have been linear, but rather, biphasic. If so, reservoir elimination would be much more difficult to achieve than Fauci and colleagues hypothesized. Margolis and Archin were also concerned, as I have been in earlier editorials,⁵ that any current antiretroviral regimen will not be able to eliminate virus in the gut-or reconstitute intestinal lymphoid tissue.

Any such clinical experiment is predicated on the assumption of viral sensitivity to multiple classes of HIV drugs. This sensitivity will not be easy to maintain. Nearly 80% of antiretroviral-treated patients with detectable viremia in one large US study had evidence of phenotypic drug resistance.⁶

Furthermore, surveillance data from British Columbia showed that emergence of any resistance was associated with mortality (hazard ratio, 1.75), with resistance to NRTIs being of particular consequence.⁷ Mortality rates were 3.02 times higher (95% confidence interval, 1.99 to 4.57) in patients exhibiting loss of sensitivity to NNRTIs than in those who did not exhibit this type of resistance.⁷ This difference may be related to issues of adherence. When patients receive unboosted PI-based antiretroviral therapy, greater than 95% adherence is required for sustained virological suppression, with emergence of drug resistance being greatest at intermediate levels of adherence (70% to 90%).⁸ However, in an observational study of patients receiving NNRTIs, there was no such clear demarcation point: virological outcomes improved in a linear dose-response manner as adherence increased beyond 50%.⁸

Finally, it must be recognized that any hope for possible HIV eradication, using our current antiretroviral armamentarium, is focused on acute seroconverters. Alhough relatively few in number and difficult to identify unless universal serological screenings are accepted, acute seroconverters are a key component of the epidemic. In fact, researchers from Quebec, using a population-based phylogenetic approach, found that those persons with acute or early infection accounted for half of forward transmission events.⁹ The maximum period for onward transmission in clusters was only 15.2 ± 9.5 months.⁹

The number of chronically infected persons is much greater than the number of acute seroconverters. In this group, using New York City––the single largest HIV/AIDS–reporting jurisdiction in the United States––as an example, the percentage of deaths due to non–HIV-
related conditions is rising rapidly and might not be altered by HIV eradication.¹⁰ Such deaths increased by one third, from 19.8% to 26.3%, from 1999 to 2004.10 Non–HIV-related mortality now accounts for one fourth of all deaths of persons with AIDS in New York City, led by substance abuse–related causes (7.4% of all deaths); cardiovascular disease (5.7%); and non–AIDS-defining malignancies, particularly lung cancer (5.0%).¹⁰ How HIV, its therapy, or both might be linked to the latter 2 conditions is a focus of active research.

So we should pursue all possible concepts for curing HIV/AIDS. But for the millions of persons living with this virus, reducing deaths will require a major shift in their health care model, with all aspects of their physical and mental health being addressed.^10,11

References:

References1. Chun TW, Justement JS, Moir S, et al. Decay of the HIV reservoir in patients receiving antiretroviral therapy for extended periods: implications for eradication of virus. J Infect Dis. 2007;195:1762-1764. Epub 2007 May 20.
2. Siliciano JD, Kajdas J, Finzi D, et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4⁺ T cells. Nat Med. 2003;9:727-728.
3. Lauerman J. Early treatment with three classes of antiretrovirals quickly reduces viral loads, study says. Bloomberg News. May 15, 2007.
4. Margolis DM, Archin NM. Eliminating persistent HIV infection: getting to the end of the rainbow. J Infect Dis. 2007;195:1734-1736. Epub 2007 May 2.
5. Laurence J. Highlights of a year in AIDS. AIDS Reader. 2007;17:107-109, 120.
6. Richman DD, Morton SC, Wrin T, et al. The prevalence of antiretroviral drug resistance in the United States. AIDS. 2004;18:1393-1401.
7. Hogg RS, Bangsberg DR, Lima VD, et al. Emergence of drug resistance is associated with an increased risk of death among patients first starting HAART. PLoS Med. 2006;3:e356.
8. Nachega JB, Hislop M, Dowdy DW, et al. Adherence to nonnucleoside reverse transcriptase inhibitor-based HIV therapy and virologic outcomes. Ann Intern Med. 2007;146:564-573.
9. Brenner BG, Roger M, Routy JP, et al; Quebec Primary HIV Infection Study Group. High rates of forward transmission events after acute/early HIV-1 infection. J Infect Dis. 2007;195:951-959. Epub 2007 Feb 16.
10. Sackoff JE, Hanna DB, Pfeiffer MR, Torian LV. Causes of death among persons with AIDS in the era of highly active antiretroviral therapy: New York City. Ann Intern Med. 2006;145:397-406.
11. Sheth AN, Moore RD, Gebo KA. Provision of general and HIV-specific health maintenance in middle aged and older patients in an urban HIV clinic. AIDS Patient Care STDs. 2006;20:318-325.