By Mark Harrington, Treatment Action Group, New York, USA

Why to start

With the demise of the HIV eradication hypothesis and the growing appreciation of the various sub-optimal realities of lifelong HAART, the issue of the most adequate time to initiate treatment with antiretroviral therapy is enjoying something of a renaissance. While the "Concorde" of triple cocktail combinations may still be a ways off (yet, unsurprisingly, less far-fetched in the UK than in the US), experts in the US have recently allowed themselves to consider the possibility that "hitting early" just might not be the irreproachable paradigm it was once believed to be. At the AmFAR AIDS Update in San Francisco in March, TAG's Mark Harrington shared his thoughts on this.

The question "When to start?" is one of the most important unanswered questions facing HIV research. Therefore, it would seem likely that researchers would be trying to answer this question. Unfortunately, for a variety of reasons, this is not the case. Therefore, we do not have much more hard evidence than we did three years ago [at the time HAART was introduced] about the best time to start antiretroviral therapy.

The Reasons for Starting Early are Theoretical

Hitting early preserves Immune function.

In general, however, immune function is fine until the CD4 count goes below 350, and, in any case, guidelines recommend starting therapy whenever someone becomes symptomatic.

Hitting early delays resistance.

Actually, since antiretroviral therapy imposes selective pressure on the virus to develop resistance, early therapy—especially if associated with non-adherence or incomplete viral suppression—may actually select for resistance. According to retrovirologist John Coffin, the only time hitting early may actually create a bottleneck in viral diversity is extremely early—within the first six months of infection.

Hitting early may speed time to eradication.

So far, unfortunately, there is no evidence that this assertion is true. With HAART alone, estimates of the time to eradication range from twelve to thirty years. [NB: Since this speech was delivered, Finzi et al. published in Nature Medicine (5:5, May 1999) their most recent estimates of the time to eradication with HAART, which range from 60 years if there are only 100,000 reservoir cells, to over 70 years if there are one million or more of these cells.]

Hitting early preserves anti-HIV Immune function, or anti-HIV CD4 cells.

Again, the evidence to date from Bruce Walker's group, the pioneer in this field, suggests this is true only when one treats very early—during primary infection and before seroconversion, in fact. Moreover, his data set is a small one. Other researchers, however, report greater variability in this cell population, suggesting it may be preserved into chronic HIV infection. [NB: In another paper in the same issue of Nature Medicine (5:5, May 1999), Picker and colleagues from the University of Texas Southwestern Medical Center in Dallas showed that "HIV-1 -specific CD4 T cells are detectable in most individuals with active HIV-infection, but decline with prolonged viral suppression." This implies that HAART actually suppresses this important CD4 population.]

Eradication of HIV from an infected individual's body is still a worthwhile goal, but it's one which appears increasingly far off and, with HAART alone, unlikely. In the meantime, could we settle—at least temporarily —for drug-free remission? It has already been achieved in a handful of cases, starting with the notorious Berlin patient (Lisziewicz et al., "Immune control of HIV after suspension of therapy," abst 351, Chicago, 1999), and continuing with a number of individuals treated during primary HIV infection and in a few treated (e.g. at the Aaron Diamond Center; see Ortiz et al, "Containment of breakthrough HIV plasma viraemia in the absence of antiretroviral drug therapy associated with a broad and vigorous HIV specific CTL response," abst 256) during chronic infection.

Ironically, in all these cases, unplanned "drug holidays" appear to have permitted a limited viral rebound which stimulated the expansion of anti-HIV CD4 and CD8 cells, which were then able to control—but not eliminate—the virus. This argues for an examination of structured drug holidays to investigate their potential to allow the immune system a chance to catch up with the virus (Waldholz & Tanouye, "Studies will see if drug 'holidays' for HIV patients could lead to a vaccine," Wall Street journal, 25.1.99; and "Pulsed therapy and structured interruptions of treatment," Project Inform Perspective 27.4.99).

Some might object that such drug holidays might encourage the development of drug-resistant HIV. So far, evidence from both Franco Lori's group and from the COMET study does not support this. (Lori et al., "Intermittent drug therapy increases the time to HIV rebound in humans and induces the control of SIV after treatment interruption in monkeys," abstract LB5, Chicago, and Neumann et al., "HIV-1 rebound during interruption of HAART has no deleterious effect on reinitiated therapy," AIDS 13(6), April 1999).

In the COMET Study, 10 antiretroviral naive patients initiated therapy with zidovudine, lamivudine, and indinavir for 28 days, followed by interruption of all drugs for 28 days and then reintroduction of the same regimen. No new resistance mutations developed during the study. The authors conclude that a one month interruption of all drugs in a HAART regimen does not adversely affect the virologic efficacy of the same regimen once reinitiated (Neumann 1999).

The Reasons for Starting Later are Practical

HAART does not completely suppress HIV replication.

Therefore, once it is started, the potential for evolution of drug-resistant virus is omnipresent. Moreover, virologic failure is common, occurring in 20%-60% of patients within two years. Although there appears to be a temporal delay, virologic failure will eventually lead to clinical failure.

Due to resistance and cross-resistance, the number of plausible, realistic, sequential, potent, tolerable and non-cross- resistant HAART regimens is either two or three.

Drug intolerance—e.g., anaemia diarrhoea, kidney stones, pancreatitis, peripheral neuropathy, psychosis, rash, Stevens-Johnson syndrome, etc.—can reduce this number still further in some individuals.

Over 90% of the new drugs in the pipeline are "me-too" drugs, which inhibit reverse transcriptase or protease. They will not work against many current or future drug resistant or cross resistant viral isolates.

The drugs are hard to take.

Less than 95% adherence virtually assures the evolution of drug resistance, as Paterson and colleagues from Nebraska demonstrated earlier this year. (Editor's note: Even with 95% adherence, only 80% of patients will not develop drug resistance.)

Long-term side effects—elevations in cholesterol and triglycerides, lipodystrophy, even cardiac infarctions are emerging.

Some appear serious. They may require additional treatments, adding to the complexity of therapy and the risk of treatment failure.

HAART is expensive.

If more people waited to start treatment until "later," the public health system could afford to treat more HIV-infected people who are not currently in care. The cost of HIV care is rising for outpatients with the addition of expensive new drugs and laboratory tests.

We will have better drugs and strategies in the future.

We will have better information in the future.

Regimens appear generally most potent if you are antiretroviral naive. As with virginity, you are only drug naive once.

HAART-induced immune restoration appears impressive in many who started therapy quite late.

(Tubiana et al., "Immunologic reconstitution after antiretroviral treatment," Presse Med. 28(8), 27.2.99). Obviously, however, it's better to avoid irreversible immune system damage and end organ disease. The cut-off of 350 CD4 cells/mm3 mentioned before, however, is earlier than either irreversible immunological damage or most serious opportunistic infections.

What Can We Do?

What strategies do activists have to encourage researchers to find out what is the best time to start antiretroviral therapy? We are encouraging researchers to:

• Develop simpler HAART regimens—twice or, optimally, once daily.
• Develop more potent HAART regimens.
• Develop rational sequencing strategies.
• Develop strategies to encourage adherence.
• Develop new antiviral compounds targeting drug resistant HIV.
• Develop new antiviral classes which inhibit new viral or cellular targets.
• Study immune activation to flush out latent HIV reservoirs.
• Study immune reconstitution to restore or augment anti-HIV immunity.
• Study immune de-activation to slow down or silence HIV reservoirs.
• Develop cheaper, quicker drug resistance assays.
• Develop cheaper, quicker assays for anti-HIV CD4 and CD8 cells.
• Study structured drug holidays.
• Study immediate versus deferred therapy in primary HIV infection.
• Study immediate versus deferred therapy in chronic HIV infection.
• Be willing to admit the uncertainty of current approaches and be willing to encourage people with HIV to make decisions to start or defer according to their own values, needs and preferences.
• Ultimately, we need to develop alliances between HIV+ people, doctors and health care workers. In order to pressure both national and pan-national Health Systems, academic researchers, drug companies and insurers (private and state) to work together to design research studies which answer some fundamental questions—when is the best time to start antiretroviral therapy, and what is the best regimen or strategy to start with?