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Why the "When to Start" Question Is Complex and Informed by Limited Evidence: A Response to Dr. Myron Cohen

March/April 2013

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Treatment as Prevention and the Risks of Merging Benefits

Even when reviewing the additional benefit from prevention, treatment guidelines are rooted in recommendations that are primarily focused on clinical need.14-16

But the impact of treatment on prevention is an area where new data is strong. Evidence includes several large and important randomised studies, showing a dramatic impact from treatment on reducing the risk of sexual transmission.

One of these studies was HTPN-052, for which Dr. Cohen was the lead investigator. HPTN-052 proved clearly that ART dramatically reduces the risk of heterosexual transmission and that the magnitude of protection exceeded that reported by condom studies alone. For this it was ground-breaking.5

But on a population level, being HIV positive does not necessarily mean that you transmit HIV. On an individual level, you may not even be having sex. You may be having exclusively safe sex, either by the choice of activity or careful and consistent condom use. Or your partner may also be HIV positive, and HIV transmission is only an issue in the context of drug resistance.


In the context of informed choice, starting earlier treatment to reduce the risk to your sexual partner(s) can be important and can improve the quality of life for both HIV negative and positive people. WHO guidelines developed for resource limited settings recommend ART at any CD4 counts for serodifferent couples to reduce transmission.18 It can reduce remaining anxiety for both partners and has given many people the peace of mind for improved sexual health. This comes from knowing that even with continued condom use, if a condom breaks, that passing on HIV is highly unlikely.

But the temptation to merge treatment benefits (probably tangible but slight at CD4 counts over 350) and prevention benefits (dramatically reduced for anyone with sustained viral suppression) needs to be resisted.

These are important caveats when considering a public health initiative to treat everyone on the premise that an HIV diagnosis equates to transmitting HIV.

Approximately 40% of ongoing transmissions may occur during primary infection (highly infectious) though this varies from approximately 10%-90% depending on the population being studied and the modelling. This is likely to disproportionately affect epidemics linked to higher number of sexual partners (such as MSM in the UK) and is likely to shift oral sex for gay men from a low to high risk. Another significant proportion of new infections relates undiagnosed chronic infection. The use of earlier treatment is unlikely to have a direct public health impact related to either of these key populations.

Dr. Cohen states that in the context of heterosexual transmission "it becomes pretty clear that treatment renders them no longer contagious" but modifies this to "nearly 100% protection when adherent" to recognise that some transmissions still occur. This ignores concerns about drug levels in the genital tract, persistent shedding, lack of data, modelling problems, cost, adherence, the "inconvenient truth" about acute transmissions. These were just some of the reasons that Dr. Cohen used to vociferously argue against "The Evangelical Test And Treat Movement" at the BHIVA conference in Autumn 2010.19

While that talk was an overly cautious and pessimistic review, it is difficult to see the volume of evidence since 2010 for such a rapid reversal in his views. Even the NA-ACCORD study -- controversial in its methodology, but often referenced as observational cohort data supporting earlier treatment at CD4 >500 had been published 18 months earlier (in April 2009).

As supported in most guidelines, access to treatment to reduce transmission should be an option at any CD4 count. The reason for this use of treatment needs to be a clear patient choice.

Health Benefits From Earlier Treatment: Does This Save Lives?

Dr. Cohen states that the HPTN-052 study had a "fairly big impact on health and survival," merging very different endpoints.

Although earlier treatment was not associated with harm, the clinical benefits were far less dramatic:

  • People in HTPN-052 were starting treatment at a CD4 count of 250 compared to 350-550. So any benefits could be driven by the low start threshold and not the benefit of treating above 350.
  • There was no statistical difference in the number of deaths between the two groups (out of nearly 900 people in each group there were 10 deaths in the early treatment group vs 13 in the group that waited until 250), with a p-value of 0.5 showing no difference and no hint of a trend.
  • There was no difference in serious "non-AIDS" events such as major organ complications and some cancers that would be expected from reducing viral load and related immune inflammation/activation.
  • Higher events were driven by extrapulmonary TB at two study sites in India, with no difference in pulmonary TB. (An important note is that in high TB settings, earlier HIV treatment may reduce the risk of new TB infections).

Survival is a life and death matter. It is clearly important to doctors and patients. Anyone saying that "immediate" treatment for everyone upon diagnosis will reduce deaths, needs evidence to show this. Merging clinical benefits (less sickness -- that is relatively minor and treatable) and survival benefits (less deaths) into a combined endpoint in this context is not helpful.

Combining survival and better health is common in studies. Better health is clearly important. But earlier treatment improved health by not getting some symptoms. Earlier treatment, in nearly all the studies in Table 1, did not reduce deaths.

Individual Responses to HIV

Dr. Cohen recognises that widely different HIV progression rates highlight a downside to universal treatment on diagnosis, but he is happy to treatment people who don't need treatment for the public good.

So while one-third of people progress rapidly, with a CD4 count dropping below 350 within two years of infection, 25% of people maintain CD4 counts higher than 500 for at lest five years and some for considerably longer.20 A much smaller percentage, called "elite controllers" also have an undetectable viral load without treatment.

This wide diversity of responses to HIV does not argue for the urgency of "immediate" treatment for everyone. The most significant assault from HIV on the immune system probably occurs within the first weeks of infection. The burst of viraemia, commonly above 1 millon copies/mL is highly infectious and decimates CD4 cells based in the gut. Despite this, most people then generate an immune response that holds HIV at bay for many years. While viraemia during chronic infection is not a good thing, and valid concern supporting earlier treatment, quantifying the associated risk has still to be determined.

Earlier treatment clearly maintains higher CD4 counts. But the example of starting at 440 compared to 220 is too easy. The context of immediate treatment needs to aim higher, and with confidence. What about starting at 1100 compared to 900. Or 900 compared to 700. After 15 years experience with ART, the best cohort studies struggle to find consistent evidence for 700 compared to 500.

Similarly, the benefits of treatment may reach a stable ceiling after five or ten years. If this is the case, the argument that over a lifetime there is little difference between 35 or 40 years on treatment becomes flawed. With no clinical urgency for treatment, this might become a difference of between 25 or 40 years, which is significantly different.

Side Effects vs Untreated HIV

The effective management of side effects is acknowledged as a caution to wider use of treatment, but the data do not exist to weight the risks and benefits. Randomised studies have not been completed and observational cohorts don't collect this data. As examples of risks, all combinations seem to reduce bone density, some people commit suicide on efavirenz, and the mechanism for fat accumulation is still unknown.

Dr. Cohen notes that there "may be adverse events (side effects) at higher CD4 counts" but says this will be balanced by the "clinical benefit [...] of protecting organs."

This issue is important -- the SMART study showed that people on treatment had fewer serious major organ complications (heart, liver, kidney) and reduced risk of some cancers, if they had a suppressed viral load on treatment, compared to people who interrupted treatment, even at CD4 counts over 350. SMART showed treatment to be far safer than was originally realised, and its results have driven a whole field of research into the implications of untreated HIV.

Damage from ongoing viral replication off-treatment is quite possible, or even plausible. Some studies have shown biomarker differences between even elite controllers and HIV negative people. But this is currently a research hypothesis and we are talking about lifelong treatment, for possible "subtle" differences.

Global Health

Global health is only briefly touched on in the interview, but this is important given that in most countries most patients have access to fewer treatment choices. Simplifying the benefits of earlier treatment irrespective of the setting has specific risks.

Concern that WHO guidelines might increase the threshold for treatment from 350 to 500 was the focus of a review in the last issue of HTB.21 These concerns are not about restricting access to treatment: WHO guidelines already recommend access to treatment for prevention at any CD4 count for serodifferent couples. They are about the risk of harm, in settings where access to resources and choices are dramatically reduced.

Wealthy settings have over 20 approved drugs from at six drug classes. Most countries base treatment on less than six drugs from two, or perhaps three classes. Access to second-line treatment is often extremely limited and is more expensive. Second-line treatment is also less effective because lack of viral load and resistance monitoring means people usually have far higher rates of drug resistance. Third-line treatment is even more rare.

Perhaps 50% of HIV positive people globally still use d4T (stavudine). The benefits of d4T-based treatment will not outweigh the risks of using it in a combination on diagnosis, at 500 or even 350. When this was the option in Western countries, the side effects were so severe that we set our guidelines at 200. When d4T is not in the combination, then 350 has the strongest evidence.

Treatment stock-outs are still common and are likely to pose a much greater safety concern than risks from HIV in someone with a high CD4 count.22-24

HIV positive people taking treatment for clear clinical benefits are most likely to have their treatment fail because of a break in their drug supply. No matter how perfect their adherence to taking meds, if there is a stock out and you are forced to stop treatment, you risk developing drug resistance as drugs levels in your blood fall during the first weeks off treatment. Restarting treatment when the supply returns will have only limited benefit for people in who resistance developed. It is difficult to see uninterrupted lifelong treatment be guaranteed when minimum financial targets for the Global Fund are missed year on year.

In the context of priority, in public health, in lives saved and health maintained, treatment above 350 for clinical benefit is not even on the radar in most resource-limited countries.

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This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.
See Also
HIV Medications: When to Start and What to Take -- A Guide From
More Research on When to Start Treatment

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