There are a few, though very few, people who are thinking clearly about 'Treatment as Prevention'. Here are a few of them.
We do not have enough evidence to recommend the big changes in national programmes needed to make treatment available for preventing infections rather than fulfilling the human right to treatment. The [him] moderator hopes that WHO does not do anything stupid when publishing its new guidelines.
[him] moderator
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"I have just sent the email below to the START Community Advisory Board of which I'm a member.
Nathan Geffen <nathangeffen@gmail.com>
Date: 10 January 2013 07:28
Subject: The implications of changes in ART treatment guidelines especially
WHO guidelines
To: Discussion regarding INSIGHT Clinical Trials research
<INSIGHTCOMMUNITY@listsrv.ucsf.edu>
The implications of changes in ART treatment guidelines especially WHO
guidelines
Several countries have changed their ART guidelines to recommend treatment
irrespective of CD4 count or at treatment thresholds of 500 CD4 cells/mm3.
The WHO is revising its treatment guidelines and it is expected that it will
change its treatment threshold to 500. WHO guidelines are extremely
important. Developing countries are guided by the WHO and activists in
these countries use WHO guidelines for advocacy.
To understand the scale of impact of the WHO guidelines, consider that there
are more people living with HIV in Nigeria than in the whole of North
America, Western Europe and Australia combined. Even a small country like
Zimbabwe has more people living with HIV than the whole of Western Europe.
Sub-Saharan Africa, Caribbean and Asian countries are strongly influenced by
the WHO guidelines, much more so than the DHHS ones in the US. This is
especially the case for countries where treatment is primarily provided via
GFATM or PEPFAR funding.
THE EVIDENCE
When considering changing the CD4 initiation threshold (or dispensing with
it entirely), we need to consider the evidence of such a change for patient
health and for prevention. Let's start with prevention.
HPTN 052 showed that ART massively reduces the risk of an HIV-positive
person transmitting HIV to his or her partner. This is supported by some
compelling observational data as well. Therefore the WHO published "Guidance
on couples HIV testing and counselling - including antiretroviral therapy
for treatment and prevention in serodiscordant couples". It is worth
recalling that the Gates Foundation delayed the WHO from publishing these
and that activists, including members of this CAB (Simon and myself),
intervened to demand that they be published.
There is also evidence from several cities including San Francisco,
Vancouver and others that reducing community viral load reduces HIV
incidence. There is also evidence from mathematical models that ART is
reducing incidence in South Africa.
Nevertheless, for many places it is not unequivocally clear that changing
the CD4 initiation threshold would have a significant effect on incidence.
In contrast to where reduction in community viral load has been shown to
reduce incidence, sub-Saharan African cities have primarily heterosexual
epidemics that are possibly in many cases saturated. On balance I suspect
that further reducing viral load will reduce incidence in sub-Saharan
Africa, but it is not a given. Moreover it has to be proven to policy makers
too because the cost implications are massive. This is why there are studies
underway, like POPART (a randomised cluster-controlled study in Zambia and
South Africa), which will look at precisely this.
Now for the treatment of the individual patient:
To my understanding, this is the salient consideration in the WHO treatment
guidelines (as opposed to the couples guidelines discussed above in which
prevention of infection of the HIV-negative partner is the salient
consideration). As Caroline Sabine and others have shown, the observational
evidence for changing the threshold from 350 is poor and does not meet the
increasingly widely adopted GRADE standard. Moreover, guidelines in some
wealthy countries have changed like a yo-yo on the issue of when to start
over the years, from hit hard, hit early down to much lower thresholds then
to 350 etc. This is precisely why the START and TEMPRANO trials are being
run - to answer definitively once and for all when the best point to start
is for patients.
One widely circulated myth that needs to be exploded is that HPTN 052 showed
that starting above 350 reduced disease progression. But the HPTN 052
initiation threshold was 250, not 350 and we have known since SMART and the
RCT in Haiti that 250 is inferior.
There are three likely outcomes of START (and TEMPRANO):
1. Earlier treatment is better because it reduces disease progression.
2. No difference.
3. Earlier treatment is harmful because of increased side-effects or reduced
adherence.
I suspect that 1 is more likely than 3. But I am much less sure about 1 vs
2. In any case, my personal prejudices, or anyone else's, don't matter. The
evidence is simply outstanding. We need to wait before making decisions.
More precisely, the WHO needs to wait. (Incidentally one thing that START
nor any other realistic RCT can measure in a reasonable period of time for
guideline considerations are the very long-term consequences of immediate
versus delayed ART.)
If 2 or 3 turn out to be the case and the WHO has recommended earlier
treatment it will undermine treatment guidelines. At best there would have
been serious cost implications for developing country health budgets; at
worst patients might have been harmed. If the WHO keeps its guidelines on
threshold unchanged and 1 turns out to be the case, then the WHO has simply
done the correct action: waited for the evidence.
THE ISSUE OF COST
Cost is profoundly important when considering public health interventions.
Activists should always be concerned about cost issues. To ignore them is
poor activism, not only because policy makers don't take activists seriously
who ignore cost, but because it is morally problematic to ignore cost.
Public health policy involves making choices determined by cost. As ART
becomes more nuanced, the relative cost per disability life-year saved
becomes higher and higher and the arguments for using the money elsewhere
become harder to refute. The organisation I've been involved in for the last
13 years, TAC, has always been cognisant of cost. That is why campaigning
for price reductions of drugs has been at the forefront of our campaigns,
why we showed in court in the PMTCT case in 2001/2002 that it would be a
cost-saving intervention and why we published research papers showing that
the rollout of ART would be affordable.
The current WHO adult ART guideline included two important changes. It
provided for treatment to be initiated at 350 and for stavudine to be
replaced by tenofovir. Both of these changes have profound cost
implications, but they are both supported by a very strong evidence base.
This means that campaigning for them is scientifically supported and there
has been partial success in getting these WHO changes adopted. WHO
guidelines should be seen as an achievable aspiration for developing
countries. Nevertheless, even today, many sub-Saharan countries initiate ART
at 200 or 250 with stavudine. This shows that cost is a critical factor,
perhaps the most critical factor, in getting poorer countries to change
their guidelines.
Changing the CD4 initiation point from 350 in the new WHO guidelines would
in my view be a serious mistake and premature. It would have profound cost
implications on GFATM, PEPFAR and developing country health budgets. We
would be willing to campaign for such a change in guidelines in spite of
cost implications if it was supported by evidence. But the evidence is still
outstanding. Expecting countries to move to a new CD4 threshold, or to
dispense with CD4 thresholds, without sufficient evidence is a serious
mistake. One argument I have heard is that some places cannot afford to even
do CD4 counts and therefore eliminating CD4 counts from treatment guidelines
makes sense for such places. This argument is easily refuted. First, it is
much more likely that such impoverished places will in fact simply ignore
guidelines and continue to initiate treatment only when patients are
symptomatic. Second there are enough places in sub-Saharan Africa that do
CD4 testing that should not have to change their guidelines simply because
there are other places that do not have CD4 counts; guidelines should not be
set on the basis of worst practice. Third, places without CD4 tests almost
always initiate with stavudine and it is probably harmful to initiate people
with high CD4 counts on stavudine.
If the WHO recommends a change with profound cost implications that is
unsupported by sufficient evidence it risks changing their guidelines from
effective advocacy documents that developing countries can realistically
aspire to into something that is unrealistic and ignored. This would be
unfortunate.
If START does show that starting treatment earlier is beneficial, then
activists will be well-armed to demand earlier treatment in spite of the
cost implications.
None of this is to say that patients who wish to start earlier and have the
opportunity to do so should be stopped from doing so. But public health
policy cannot be guided on the basis of what some private-sector (or
otherwise fortunate) patients are able to do."
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12.14.12
Untangling HIV Treatment as Prevention
Katharine Kripke & Farley Cleghorn
Since the publication of the results of the HIV Prevention Trials Network (HPTN) 052 trial,1 “treatment as prevention” has become the new buzzword in the HIV/AIDS field. Advocates are hailing it as the beginning of the end of AIDS, researchers are talking about it at conferences, and countries are adding it to their national strategies. But there seems to be confusion as to what constitutes “treatment as prevention” and how it should be implemented programmatically.
HPTN 052, a randomized, controlled trial with HIV serodiscordant couples, in which the HIV+ partner was randomized to start on treatment when their CD4 count was between 350 and 500, or to wait until their CD4 count fell below 350. Among those in which the HIV+ partner had a CD4 count between 350 and 500, those who received Highly Active Antiretroviral Therapy (HAART) had a 96 percent lower rate of transmission to their uninfected partners compared to those who did not receive HAART.
Jia, et. al.2 recently published a study in the Lancet suggesting that in a real world setting, HIV treatment can reduce HIV transmission by 26 percent. They attempt to relate these results to the HPTN 052 trial and to the (World Health Organization) WHO recommendation that antiretroviral therapy be offered to all HIV-infected individuals with uninfected partners of the opposite sex (serodiscordant couples) to reduce the risk of transmission. While the Jia, et. al. results are certainly useful, they cannot really be compared with HPTN 052, and it is debatable whether the study can claim to be an analysis of treatment as prevention.
The Jia, et. al. study was a retrospective observational cohort analysis, in which they compared the transmission rates within serodiscordant couples in which the HIV+ partner either received treatment or didn’t receive treatment. An important point to note about this study is that in this cohort, those receiving treatment were receiving it for their own health based on China’s treatment guidelines, unlike in HPTN 052, which was comparing treatment to no treatment among those with CD4 counts above 350 and no AIDS-defining events.
While treatment of an HIV+ person for their own health may also prevent an individual from transmitting HIV to others, we believe it is confusing to refer to this as treatment as prevention. To keep from comparing apples to oranges or causing confusion, we would like to propose that the term “treatment as prevention” only be used to refer to the provision of HAART to HIV+ people who do not qualify for ART for their own health based on the WHO guidelines, or country policy, if they differ. We suggest that “treatment as prevention” should not be used to refer to treating people with CD4<350, or for provision of ARV drugs to HIV-uninfected people, which is more appropriately referred to as pre-exposure prophylaxis (PrEP).
Once defined, the question remains - how should treatment as prevention be implemented, and who should be included? Some3 have suggested that all HIV+ people should be put on HAART for life as soon as they test positive. Given that treatment coverage in low- and middle-income countries is still at 54 percent,4 it seems for now that scaling up treatment for those who need it urgently for their own health should remain the priority. For countries struggling with limited resources, it is a human rights issue to ensure that the excitement about treatment as prevention does not end up siphoning resources away from providing treatment to people with advanced HIV disease. Keeping the focus on treating those in urgent need will still result in prevention benefits, as suggested by the Jia, et. al. paper. A recent study published early online by Bärnighausen, et. al.5 finds that the combination of scaling up voluntary medical male circumcision along with ART for those who need it for their own health is more cost-effective than a treatment as prevention approach, both in terms of infections averted and mortality.
Additionally, the health effects of treating people with CD4>500 are still unknown. While HPTN 052 demonstrated a clear clinical benefit to patients of initiating treatment between CD4 350-500, it is yet unknown whether the effects of starting treatment sooner will be helpful or harmful. The START trial,6 whose results are expected in 2015, seeks to answer this question. In the meantime, it is prudent to avoid claims that providing treatment to all HIV+ people is better for their health.
In light of the uncertainties, policy- and decision-makers may be best advised to carefully interrogate the risks and benefits as they consider implementing treatment as prevention strategies as part of programs. For countries that have succeeded in scaling up ART for those already eligible, spending additional resources to pilot treatment as prevention approaches may be a wise investment. However, there are numerous complex issues they will have to consider before moving ahead. They will need to determine how they want to target these programs: discordant couples? Pregnant women? Will they stratify by CD4 counts below 500? How will they allocate prevention resources to these programs compared with other prevention approaches? Will they consider cost-effectiveness of treatment as prevention programs compared with other prevention interventions? They will also need to consider how to measure the outcomes and impact of these programs. What kinds of surveillance will help them understand if such a strategy is working? Tracking HIV incidence is challenging for most countries but can be done using cross-sectional methods such as the “detuned” assay. Do measures such as “community” viral load have a role is such assessments, as has been shown in parts of North America?7
The emerging evidence about treatment as prevention is potentially a game changer and has helped to diminish the polarization between treatment and prevention within the HIV field. To remain on track to eliminate HIV as quickly and cost-effectively as possible, countries should take a measured approach based on their own unique circumstances, such as prevalence, ART scale-up, and resources available and required. As evidence continues to emerge, the HIV community will be wise to avoid the temptation to jump on the bandwagon of the next big thing and carefully consider the programmatic, economic, and human rights implications of treatment as prevention.
REFERENCES
Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. The New England journal of medicine. Aug 11 2011;365(6):493-505.
Jia Z, Ruan Y, Li Q, et al. Antiretroviral therapy to prevent HIV transmission in serodiscordant couples in China (2003-11): a national observational cohort study. Lancet. Nov 30 2012.
Granich R, Crowley S, Vitoria M, et al. Highly active antiretroviral treatment for the prevention of HIV transmission. Journal of the International AIDS Society. 2010;13:1.
UNAIDS World AIDS Day Report 2012. UNAIDS; 2012.
Bärnighausen T, Bloom DE, Humair S. Economics of antiretroviral treatment vs. circumcision for HIV prevention. Proceedings of the National Academy of Sciences. December 6, 2012 2012.
Babiker AG, Emery S, Fätkenheuer G, et al. Considerations in the rationale, design and methods of the Strategic Timing of AntiRetroviral Treatment (START) study. Clinical Trials. April 30, 2012 2012.
Das M, Chu PL, Santos GM, et al. Decreases in community viral load are accompanied by reductions in new HIV infections in San Francisco. PloS one. 2010;5(6):e11068.
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