New Evidence Supports HIV Treatment During Acute Infection

In 1995, Sabine Kinloch-de Loës and colleagues¹ reported on the benefits of zidovudine (AZT, Retrovir) monotherapy given for 6 months during the course of primary HIV infection. Since then, some researchers have advocated that highly active antiretroviral therapy (HAART) should be offered to all patients who are identified during the first few months following their acquisition of HIV infection. Their reasons were as follows:

1. During acute infection, the viral reservoirs have not yet been completely established, and early therapy will interrupt this process.

2. A patient's immune system during acute infection is still largely intact, and it is likelier to remain so with HAART.

3. At the time of acute infection, the viral isolates are still quite oligoclonal and more amenable to control by a patient's immune system; intervention with HAART (before significant viral diversification occurs) may perpetuate this state.

However, there could be significant consequences to this approach. In addition to the simple inconvenience of having to take pills every day, there is always the risk of short-term and long-term toxicity. Perhaps, more importantly, with treatment there is the risk of developing drug resistance and, as a result, limiting future therapeutic options.

This situation, of course, can be avoided completely if HAART is not used at such an early stage, when its benefit is probably marginal at best. The latter point is key, as some would argue that there is still limited rationale and no controlled clinical trial data to support the recommendation to use HAART in acute HIV infection.

The final plenary of the 12th Conference on Retroviruses and Opportunistic Infections was entitled "Making Sense of HIV Pathogenesis" (Plenary 127). In it, Daniel Douek, Human Immunology Section Chief at the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases, presented convincing evidence that HIV itself, either directly or indirectly, causes the loss of CD4+ cells and other damage that ultimately leads to AIDS. More interestingly, Douek showed data to support the theory that a significant proportion of CD4+ cell loss occurs at the earliest stage of disease: during acute infection.

In the gastrointestinal tract, for instance, there is virtually a complete loss of lymph tissue during acute infection due to the extensive destruction of CD4+ cells, and the body never fully recovers from this loss.

This finding adds to evidence that suggests that, if you intervene with HIV treatment during acute infection, this loss of lymph tissue can be prevented from occurring, perhaps forever. Although this study does not provide conclusive evidence regarding the use of HAART in this setting, it certainly bolsters the rationale for a careful trial to be performed to resolve this issue once and for all.

Speaking of clinical data, Frederick Hecht, from the University of California-San Francisco, and colleagues presented information on 13 individuals who received HAART during the most acute phase of infection (less than 2 weeks after seroconversion), and another 45 people who were treated within the first 6 months after becoming HIV infected (Abstract 568).

Treatment was later discontinued, and study participants were evaluated up to 72 weeks later. They were then compared to 337 patients who had been diagnosed within the first 6 months of infection but who were never treated.

The 13 patients who had begun HAART during the acute phase were found to have 5 times lower plasma viral load and a CD4+ cell count that was 125 cells/mm³ higher at 72 weeks after stopping therapy, when compared to untreated patients.

Even the second group of patients who had been treated after the 2-week acute phase following seroconversion, but within the first 6 months, showed improvement; their CD4+ cell count was 76 cells/mm³ higher than it was in untreated patients.

The potential benefits of treatment were corroborated with data on similar patients from the PRIMO cohort (Abstract 571), which demonstrated evidence of disease progression over 2 years in 27 of the 75 patients (36%) diagnosed with acute or early HIV infection who did not receive HAART. Perhaps the situation would have been different had HAART been prescribed at the time of initial presentation?

Treatment During Acute Infection

Atazanavir Plus Stavudine and Didanosine

So, if you're going to treat a patient during the acute infection stage, how do you do it? Constance A. Benson, from the University of Colorado Health Sciences Center, and colleagues (Abstract 570) used atazanavir (ATV, Reyataz)-based therapy.

At 48 weeks, the 37 treated patients had a median CD4+ cell count of 725 cells/mm³, compared to a median CD4+ cell count of 496 cells/mm³ in the 18 untreated patients. However, the nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone of stavudine (d4T, Zerit) + didanosine (ddI, Videx) that was used in this study is no longer a recommended regimen. It would be hoped that the use of a more appropriate combination would lead to better results.

HAART Plus Hydroxyurea

Is there anything in addition to HAART that could help acutely infected patients? Some researchers had thought that adding hydroxyurea (Hydrea) to HAART would be helpful, in order to reduce the immune activation that may fuel viral replication in the circulation and in tissue stores. Mark Bloch, from Holdsworth House General Practice in Sydney, Australia, and colleagues investigated this strategy (Abstract 569). As shown in 33 patients, however, the addition of hydroxyurea does little except suppress CD4+ cell counts in the weeks after it is started. Over 2 years, there was no clinical, virologic or immunologic benefit.

Cyclosporin A

Another way of reducing immune activation is with a drug like Cyclosporin A (known generically as cyclosporine), which was given, along with HAART, to 34 individuals with acute or early HIV infection in a study by Gian-Paolo Rizzardi, from the Scientific Institute San Raffaele in Milan, Italy, and colleagues (Abstract 567).

After 56 weeks, the patients who had received HAART and Cyclosporin A had a higher CD4+ cell count than the 43 patients who got HAART alone (440 versus 280 cells/mm³). Cyclosporin A patients were also more likely to have a plasma viral load below 50 copies/mL (96% versus 70%).

Although this small study presents encouraging results, the widespread implementation of this approach is limited by the toxicity of Cyclosporin A. This includes the risk of significant impairment in renal and hepatic function and the fact that Cyclosporin A must be administered intravenously. In addition, blood levels must be closely and repeatedly monitored to ensure therapeutic levels are present as well as to avoid toxicity. Nonetheless, this small study suggests that additional strategies in combination with HAART may enhance the benefits of treatment, particularly in this setting.

Mycophenolate Mofetil

Yet another potential approach to reducing immune activation is the use of mycophenolate mofetil, also known as MMF or by the brand name CellCept. In a study (Abstract 514) by Giuseppe Tambussi, also from the Scientific Institute San Raffaele in Milan, Italy, 15 patients who had initiated therapy during primary HIV infection and who had maximal virologic suppression were given 500 mg twice daily of mycophenolate mofetil for 2 weeks. HAART was then stopped and only the mycophenolate mofetil was continued for another 24 weeks.

Only 3 of the 15 patients had to restart HAART within the next 3 to 4 months due to a plasma viral load over 100,000 copies/mL, compared to 4 of the 6 individuals who had not received mycophenolate mofetil before restarting HAART.

These data would need to be replicated in a larger study before the approach could be advocated on a more widespread basis, but they certainly support the line of reasoning that reining in the immune system may be a good adjunct to HAART if the latter is to be used to maximum advantage in primary HIV infection.

Summary: Consider Treatment During Acute Infection

From a clinical point of view, none of the data presented at this meeting are conclusive. However, they do present strong evidence that contradicts those who state that the issue is resolved, and that treatment should never be considered at the earliest stages of HIV infection.

The take-home message is this: If you have patients recently infected with HIV (within the past 1 to 12 months), make sure they consider treatment! Irreversible damage may be occurring if treatment is delayed until much later. This is true irrespective of a patient's CD4+ cell count.

If a patient is not sure whether he or she wants to start treatment, have the patient consider going into a clinical trial, if possible. There are trials currently enrolling that are looking at controlling immune activation to help make HAART work better, or limiting courses of therapy (9-12 months) followed by a treatment interruption, with the hope of maintaining a favorable steady state off treatment, perhaps indefinitely.

Most of these studies have a control arm consisting of untreated patients to ensure that the risks and benefits of treatment in this setting are rigorously ascertained. From the patient's perspective, it is our job as healthcare providers to make sure patients understand their options. Acute HIV infection only comes around once, and it may well be a unique opportunity to intervene.

Footnote

1. Kinloch-de Loës S, Hirschel BJ, Hoen B, et al. A controlled trial of zidovudine in primary human immunodeficiency virus infection. N Engl J Med. August 17, 1995;333(7):408-413.