The cure: are we any closer?

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Post by Neil McKellar-Stewart31 May 2013

These days, most PLHIV are able to achieve an undetectable viral load within three months of starting treatment and to sustain that level indefinitely.

The benefits that modern antiretroviral (ARV) treatment provides, including reducing infectivity and strengthening your immune response, are well known.

However, a strengthened immune response does not automatically mean a normal one. Even when immune system markers are restored to the normal range (800-1500 CD4 cells per mm³ of blood), these CD4s, CD8 T-lymphocytes and B cells — key elements of an effective response to infection — may still produce an inadequate immunological response.

Modern HIV treatment is highly effective and life-changing, but it suppresses rather than eradicates HIV and it is therefore necessary to keep taking it for life. The effects of stopping treatment are very clear: viral replication, viral load and HIV-associated inflammation will all increase, often within weeks, as will the risk of developing cardiovascular, kidney and liver disease.

Add to this lifelong need a constant rise in numbers of PLHIV and we have a growing global therapeutic and health service funding challenge.

The case for a cure is obvious and pressing.

WHAT MIGHT A CURE LOOK LIKE?

A cure might take two forms: the elimination of all HIV-infected cells within the body (a sterilising cure); or, alternatively, the generation of effective immunity to HIV, resulting in lifelong control of HIV in the absence of antiretroviral treatments (a functional cure, in which HIV is controlled by normal physiological processes rather than just suppressed by drug treatments).

A functional cure also requires three other factors:

  1. effective immune function restored and stabilised;
  2. a massive decrease in HIV-induced inflammatory processes; and
  3. risk of HIV transmission reduced to zero.

SOME OF THE COMPLEXITIES: RESERVOIRS AND LATENCY

Within a few days of initial infection, HIV is established in reservoirs within the body.

These are sites or cell types in which HIV persists. Such cells contain HIV, which has been integrated into their DNA and in which normal replication processes generating new HIV viral particles have been blocked or ‘silenced’. Such cells are said to be latently infected or resting: they contain pro-viral DNA. These T-cells are relatively long-lived — in some cases years — and are part of the pool of memory cells that provide protection from bacteria and viruses  with which we are threatened throughout our lifetime.

ARVs interrupt the replication cycle of HIV at a number of points, depending on their class — for example, nucleoside reverse transcriptase inhibitors, integrase inhibitors, protease inhibitors and so on.

However, they are only effective in T-cells that are active (not resting), and in which HIV is actively replicating. ARVs do not affect cells that are latently infected with HIV and in which active viral transcription has been silenced.

Effective early treatment results in decreased total amounts of HIV RNA and reduced numbers of cells in which HIV has been integrated into the host DNA. There are fewer infected cells and a reduced reservoir of HIV-infected cells. But even with very early, intensive treatment, once infection is established, reservoirs soon develop.

HIV may be present in a range of reservoirs: in CD4 T-cells in the gut and lymph nodes; in blood in long-lived memory T-cells; in a range of other cell types, including naïve CD4 cells not yet active in the immune system; and in specialised cells in the central nervous system.

A cure for HIV will require that cells containing pro-viral DNA are either eradicated entirely from reservoirs (perhaps not achievable) or at least reduced so much so that the immune system is able to deal with them. Purging these reservoirs will require the latent provirus DNA in infected cells to be stimulated (switched on). Such cells when stimulated will either die from the destructive effects of the virus or be cleared by host immune defence mechanisms.

At least three approaches have been proposed to purge HIV out of latency:

  1. Stimulate the main host transcription agent, which facilitates HIV replication. That is, activate resting T-cells as a whole. Several drug and other agents have been suggested, some of these, such as interleukin-2 (IL-2), have been unsuccessfully trialled. This approach is risky, with possible unintended consequences. Generalised CD4 T-cell activation carries a major risk of generating a cascade of inflammatory molecules that may be harmful to a range of organs and may make the patient very ill.
  2. Inhibit the action of complexes, including histone deacetylase, which block HIV DNA transcription. Several agents have been proposed, including valproic acid (trials have been unsuccessful); vorinostat (currently being trialled); and newer more potent agents: romidepsin, panobinostat, givinostat and belinostat.
  3. Use a combination of these two approaches, stimulating transcription and inhibiting the compounds blocking it.

Additionally, a range of molecules on the surface of both CD4 and CD8 memory cells may limit their ability to activate effective immune responses so that HIV-infected CD4 cells are recognised and killed. A cure will probably require addressing the role of such molecules.

BUT THERE’S MORE: DEALING WITH RESIDUAL VIRAL REPLICATION

Once HIV has been purged from its reservoirs, the problem of low-level residual viral replication must also be dealt with. HIV infection causes ongoing inflammation and activation of the immune system, in particular in lymph tissues, where any residual HIV may continue to infect activated T-cells. Such inflammation must be controlled and immune responses enhanced, perhaps through a therapeutic vaccine. All this suggests that a cure will involve resolving numerous issues, some of which are poorly understood.

THREE EXAMPLES OF WHAT A FUNCTIONAL CURE MAY LOOK LIKE

  1. THE BERLIN PATIENT, a 40-year-old HIV-positive man who was responding well to antiretroviral therapy, developed leukaemia and needed a bone marrow transplant. He was successfully transplanted with a bone marrow containing T-cell surface receptors to which HIV was not able to attach. His HAART was discontinued at the time of the transplant and now, up to six years later, detectable HIV RNA has not re-emerged.

    As well as the reconstitution of his immune system with cells not able to be infected with HIV, there are other factors that may have contributed to this apparent cure. They include the possible reduced size of the HIV reservoir caused by treatments preparing for his transplant and the use of immune-based therapeutics afterwards, which may have prevented low-level HIV replication and subsequent virological rebound. This is a unique case using costly and life-threatening techniques, which are not feasible to apply generally.

  2. At CROI 2013, there was the case of a PREMATURE BABY who tested positive to HIV RNA and DNA in two separate blood samples within a day of birth. (The mother was diagnosed with HIV infection at the same time.) The baby commenced normal therapeutic HIV treatment within 30 hours after birth. HIV was detectable on days seven, 12 and 20 but thereafter became undetectable for 18 months, presumably in response to effective HAART. At this point, the infant was lost to regular care (and thus treatments). The child re-presented and at 24 months, in the absence of treatment for six months, still had an undetectable VL. A single copy of HIV RNA in plasma was detected.

    Replication-competent virus was undetectable in resting CD4 T-cells, and finally at 30 months, after receiving no treatment for 12 months, HIV RNA and DNA, together with HIV-specific antibodies, all remained undetectable. If this child continues to live with seemingly controlled (and undetectable) HIV, this will probably constitute a case of a functional cure.

  3. The third example involves 14 patients in the VISCONTI COHORT (Viro-Immunological Sustained CONtrol after Treatment Interruption). This cohort consisted of PLHIV from three separate French studies. It included 14 patients who were diagnosed very early and who commenced HAART within two months of infection. These 14 participants took an average of three months to achieve undetectable VL. They all remained on treatment on average for 36.5 months, during which time their median CD4 counts rose 400 cells/mm³ to an average 930. They then interrupted their treatments — not currently supported by treatment guidelines — after which time they were able to maintain an undetectable VL for an average of 89 months with no viral rebound and maintain average CD4 counts of 837 cells/mm³.

    In some ways, the Visconti cohort look like the very small percentage of people with HIV who are able to naturally control their HIV infection over many years. However, they differ from such ‘elite controllers’ in several significant ways. They have genetic immune markers, which are associated with a risk of HIV progression, and, in contrast to elite controllers, possess few markers that might protect them from HIV progression. They have very weak or undetectable CD8 T-cell responses, and their capacity to suppress HIV is low. So, genetically and immunologically they are quite distinct from elite controllers. However, like elite controllers, their HIV reservoir levels, as measured by HIV-infected resting memory CD4 T-cell subsets are low, and continue to decline.

    These 14 individuals, now called post-treatment controllers, represent an example of what a functional cure might look like.

    Undoubtedly they will be monitored for many years.

    From this large cohort of French PLHIV followed from 1997 to 2011, only 756 began treatment within six months of infection and received at least one year’s treatment. Of these, 70 ceased treatment and had subsequent viral rebound. While these results certainly add to the growing evidence of the benefit of early initiation of treatment, the study authors suggest that even for individuals who begin treatment very early, within six months, the probability of being able to maintain an undetectable VL if treatment is ceased is only 10-15%.

    The vast majority of PLHIV even those who are diagnosed and commence treatment at the very earliest, that is, within two months of infection, will need to stay on treatment to control their HIV. The overwhelming consensus of HIV clinicians is that once commenced, treatment should not be discontinued. The 14 cases in the Visconti cohort are exceptional, and provide no argument for stopping treatment, at least until more is understood about how they were able to control their HIV infection.

WHAT DOES THIS MEAN FOR PEOPLE RECEIVING HIV TREATMENTS?

Advances in understanding the nature and size of HIV reservoirs continue to be made, and the evidence of the benefit for limiting reservoir size by very early treatment has also been advanced. However, the task of purging HIV from its reservoirs proceeds slowly.

So, are we any closer to finding a cure? Yes. But are we there yet? Sadly, no.

While we wait, our best bet is to maintain our health by suppressing the virus on treatment and doing all the other things necessary to stay well. 

And keep watching this space.