Gallant et al’s editorial on ART guidelines in resource poor settings

I’m going to take Joel Gallant (who I greatly admire) and colleagues to task a bit for the *tone* and timing of their just published piece in CID, “Universal Antiretroviral Therapy for HIV Infection: Should U.S. Treatment Guidelines Be Applied to Resource‐Limited Settings?”, which states that “new U.S. guidelines recommending ART for all HIV‐infected patients should not yet be universally applied to resource‐limited settings because of the uncertain safety and efficacy of doing so resulting from disparities in the regimens used, capacity for monitoring, and the ability to provide uninterrupted ART.”

To which I must respond: No fake Jake. Everyone already knows that. But we’ve got to move in the direction of one global standard of care. Why didn’t you rather start of with your concluding discussion about what must be done to remove “the glaring disparities among nations that stand as obstacles to the ethical implementation of early ART.”

We agree on many of the things that must be done:

•”fostering political commitment at a country level to sustain HIV treatment programs, with reduction in dependence on external donor support;
• development of low cost viral load assays to assess adherence and detect virologic failure [point of care preferably – TS];
• increased use of less toxic regimens for first‐line therapy; expansion of options for first‐ and second‐line therapy [and critically third and fourth line -don’t think small -TS] including integrase inhibitors and less toxic protease inhibitors;
• development of less demanding delivery systems that simplify provision of ART for patients and that reduce treatment interruptions; and
• public education about the rationale for initiation of therapy before the onset of symptoms.

Absolutely. Many of us have been working on these things for years. Our goal is to leverage new WHO guidelines (which are not yet the US guidelines of treatment for all PLHIV) to push towards one high global standard of care… not to simply say: “we’re not ready — but rather what must be done to get there within the next few years.”

Which why I’m not so gung-ho on the study idea any more. I have reached the conclusion that it would be a Tuskegee-like experiment… and its conclusions irrelevant the moment countries get additional low cost, simple to administer ART regimens or POC viral load — which must happen in the near future — not 5 years down the road.

The release of this paper is ill-timed, just weeks before the new WHO guidelines come out. The tone is defeatist rather than aspirational. We cannot allow the status quo to continue. We must move forward and the new WHO guidelines move us the first step in that direction. We must take the next.

31 thoughts on “Gallant et al’s editorial on ART guidelines in resource poor settings”

  1. Theo,
    Thanks for your thoughtful comments. It comes down to this: If you were advising someone with a CD4 count of 750, or even 500, whether to start ART, and that person lived in a country where they were still using d4T, were not monitoring viral loads, had no access to resistance testing, had limited second-line options, and where there were frequent drug stock-outs, would you advise that person to start treatment or to wait? Would you start if it were you?

    As a physician, I have to weigh the risks and benefits of treatment on an individual level. I can’t prescribe based on what’s good for society or for the epidemic if it means harming individuals.

    As for the timing of the article, I think it’s very appropriate to stimulate this discussion now. Of course we would have liked to have published this earlier, but that’s not always under the control of authors.

  2. OK–even if you frame it that way that we have two standards of care according to personal income (which I disagree with since it is the same canard that was used before we provided ART in Africa), then if your patient with HIV was living in an environment with sky high rates of TB or X/MDR and other pathogens with a dubious health care system and a 10-20 percent fatality rate would you still advise that they wait? Observational studies suggest that the cumulative risk of waiting until 350 or 500 can be significant. What level would you accept for your partner or your child?

  3. Francois Venter

    I completely agree – the push for higher initiation CD4 counts, ignoring the reality of the treatment programmes on the ground, seems poorly thought through

    1. The idea of this *patient* presenting with 750 CD4 cells then engaging with the health system and being retained as a well patient simply does not reflect the reality on the ground in sub-Saharan Africa. No one is saying everything is in place on the ground yet, but we have got to make it happen. If we had that same attitude ten years ago we wouldn’t have the programme now in place. Meanwhile half the people who don’t qualify for care never come back once they are sent away.

      It isn’t so much the substance of what Joel says needs to be done that I disagree with. It is just attitude that everything has to be in place before anything should happen. What we should be saying is that ‘PLHIV should be offered first rate SOC ART when they are ready for it,’ and ‘here is what must be done to do it safely and effectively.’

  4. I agree completely with the idea of first rate SOC ART, but that’s not what I see in most of the countries I spend time in. The danger is in applying first-rate SOC “when to start” standards long before we have first-rate SOC drugs and monitoring in place. Such an approach might be good from a utilitarian, “greatest good for the greatest number” standpoint, but it could harm many individuals who would have been better off waiting for better drugs and monitoring. It’s fine to say that under optimal circumstances we should treat everyone. But in countries that are still using up their stockpiles of d4T with monitoring consisting of twice-yearly CD4 counts, early initiation could do more harm than good. And if people starting ART with CD4 counts of 500 end up with anemia, neuropathy, or lipoatrophy, it’s not going to be a ringing endorsement for treatment among those who have not yet started. It could end up having the opposite effect: turning public sentiment against ART.

    1. You are absolutely right that early treatment should not be started with nevirapine or d4T containing regimens We are arguing past each other.

      I am saying we have become complacent with the two different standards of care that are becoming entrenched — with the idea that we can’t have the second, third and fourth line regimens that people have in the industrialised countries… WHY DO WE HAVE TO ACCEPT THIS? We should put out guidelines that say PLHIV have a RIGHT to *THIS quality of care*, and WE ALL have a responsibility to make it happen. It will take a lot of work. I am not suggesting going forward with something that is dangerous or substandard… We have to say: THIS IS WHAT THE STANDARD SHOULD BE: now this or that country has to phase out these drugs and commit to adequately supporting their health system or they are giving their people a lower standard of care and violating their right to health. People have to mobilise, countries like South Africa have got to help/combine their purchasing power with their neighbours. Flexibilities in TRIPS MUST be utilised.

      Rather than simply put up a STOP sign on the new WHO guidelines (which are not the US guidelines ), before they have even been launched, we should seize the moment and recommit ourselves to universal access and to a human-rights centred approach to HIV-care and treatment.

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  6. Francois Venter

    No one is debating that we have to push for better systems of care (and you know thats what I do as my job), but ‘the programme we have’ also includes routine drug stock outs with treatment interruptions, substitution of TDF with d4T and AZT all the time, and a few weeks ago, in a clinic in central Joburg, substitution of the FDC with d4T/NVP dual therapy. Its not useful to dismiss a legitimate concern that the benefits (and many observational studies show minimal or no benefit with early treatment) may not stand up to the realities on the ground. PS – the VCT programme in SA has been a huge success at identifying people early on, with almost 20 million people testing in the last 3 years, and CD4 count at initiation in my clinics has more than doubled, to around 200 – and yes, you are right, LTFU is high if ART is not initiated (its much more than half) – but its a tough call that this justifies earlier treatment, esp when LTFU past initiation also is a problem.

    1. I disagree that studies have shown minimal or no benefit with early treatment – the issue is that the studies that can show CLINICAL ENDPOINT data — we are talking death and morbidity — have not been done, but there are plenty of studies that show virological/CD4 cell benefit. With long enough follow-up these things should be correlated — if we have the ART regimens available — and that IS a big if that we have to secure — but then there would be no question that preventing progression doesn’t translate to better clinical endpoints PLUS it helps a person protect their loved ones from HIV.

      That being said, Francois, I respect your complaints about the downsides of the system that you have. But PLHIV should be told that there is a higher quality of care available globally… if they want to go on treatment when they present, tell them the risks with what is available in the context where they live, and then LET THEM make the decision. Moreover, we need to mobilise the community to fight to address these issues, to insist on a commitment to better primary health care generally.

  7. Francois Venter

    Caroline Sabin has a good recent review in AIDS on this (Rating evidence in treatment guidelines: a case example of when to initiate combination antiretroviral therapy (cART) in HIV-positive asymptomatic persons) . And yes, its saved over 2 million lives, because it used an evidence based intervention that worked so effectively, it could withstand poor health delivery.

  8. Theo, the fact that ART increases CD4 count and decreases viral load doesn’t make a very convincing case. Of course it does those things, but it becomes harder to show clinical benefit at high CD4 counts because people with high CD4 counts are unlikely to have bad outcomes to begin with. That’s the reason for the inconsistent results in large cohorts, and the reason, in part, why the DHHS and IAS-USA recommendations for ART have weaker ratings for those with high CD4 counts than with low CD4 counts. The DHHS guidelines committee struggled with the recommendation for universal ART, and in their earlier version, opinion was a divided opinion among the panelists. The current recommendation to treat everyone regardless of CD4 count was ultimately made because there is some evidence for clinical benefit, strong evidence for prevention benefit, and little evidence of harm using current drugs. That relative lack of harm clearly does not apply in the places we’re discussing. Tell me again what you would recommend to an asymptomatic person with a CD4 count of 499 who was being asked to start a d4T + NNRTI-based regimen with monitoring consisting of CD4 every 6 months and the potential for stock-outs? I sure as hell wouldn’t start ART under those conditions, which makes me wonder which is the more paternalistic approach? It seems that you’re suggesting we ask people in resource-limited settings to do something that U.S. experts wouldn’t consider for themselves. You mentioned being a patient advocate. If we’re advocating for patients, then we may have to put aside public health considerations and focus on whether the risk:benefit equation is favorable or unfavorable for the individual.

    It became clear that saving lives by treating HIV in developing countries was a moral imperative. The same cannot be said of treating people early with outdated drugs and methodologies. I am as big a proponent of ART as anyone; I just want people who take it to experience more benefit than harm.

    The possibility of offering the “same global standard of care” is pie in the sky: it ain’t going to happen any time soon. Until it does, we have to protect individuals from the unintended consequences of overzealous and unrealistic public measures that don’t take individual risk and benefit into account.

    1. I think that is the same canard that said we’d never be able to introduce ART into resource limited settings in the first place… and in many ways, care in resource limited settings may actually have pushed the boundaries of care in industrialised countries… and I’m talking about adherence support and reducing monitoring/demedicalising care somewhat … which is essential for long term chronic care. Remember monthly viral loads?

      But in truth, we want the same things, we just disagree on how to get there. I don’t want people to go off irresponsibly starting all comers on treatment in the current healthcare system mucked-up reality we have. But I think that the status quo is not acceptable and we MUST move forward.

      We have lost the momentum we once had. I fear we have caved in, conceded defeat. I, and a number of the leading INGOs, ASO and networks of PLHIV are committed to using WHO’s new guidelines as an impetus moving forward RESPONSIBLY — trying to make sure that people are not harmed by thoughtless aggressiveness. There is some of that out there, I know. But we agree on what must be done to do deliver on a standard of care that may not be as individualised as in the global North — but which may very well achieve a similar if not better outcome.

      But please don’t be so engaged in defending an argument that we lose this opportunity and wind up simply defeated and accepting the status quo. There are a number of reasons why people should have the opportunity to choose earlier treatment… And our own should not be telling us it is not possible. What we did 10 years ago must be repeated. How else do you think we will get there if we do not declare that something better is out there, and it is a human right?

      I’m disappointed if this is where we end it…. if we say, ok, we will only treat the privileged who are able to access and be retained in care when they present at ‘just the right time’.

      But I’m all for calling out those who are just steam rolling ahead foisting a harmful SOC onto PLHIV with few other options. Steps A, B, C, and D have to be in place… but I don’t think we will get there without some forward momentum.

    2. But Joel, I didn’t answer your question about if d4T and nevirapine were part of the frontline regimen. The guidelines should state that people should be given the choice to access earlier treatment with safer regimens that are being used for first line in many countries, with secure access to second and third-line regimens in case of supply chain problems etc… and that they may need to demand that as a human right. This is what has to be done… we’ve lost the fire in our belly, and simply saying it is pie in the sky isn’t going to get anyone anywhere.

  9. Great, then it sounds like you’ve come around to my point of view :) We should use state-of-the-art starting criteria when we have state-of-the-art therapy to go with it. I have no argument with you there, but implementation and affordability are the obvious obstacles, no matter what people might “demand” as a human right.

    1. I never disagreed with you on that point. In fact, I’ve long said that if there was only one treatment regimen, it would be crazy to start early. I just think that we are on the cusp of multiple regimens and we need a concerted effort to push for them to become affordable. If TAC and others had not demanded access/used human rights based approach to treatment before, if WHO had not put out the forward thinking 3X5 Initiative [which was WAY ahead of its time, and could have been called highly impractical given that there was very little in the way of supply chain management, lab capacity etc, in place,] we would not have 9 million people currently on ART. My whole point is, how do we get the process going?

      I think we need to use the new WHO guidelines to speak truth about what OUGHT to be done as a catalyst. And they could give programme managers a lot of wiggle room to not do a darn thing. But I believe in PLHIV and community empowerment. I think we need to tell people, well, in the rest of the world, people can start treatment whenever because they have safer first, second and third-line regimens, but it wouldn’t be advisable for you, because your programme still uses d4T.

  10. Our editorial was intended to do exactly that (get the process going), but you didn’t like it! There are many people and groups working on this–trying to update guidelines with respect to drug choices, trying to come up with cheaper point of care viral load assays, trying to point out the problems with CD4 monitoring, and trying to expand access to safer drugs. The point of our editorial was to suggest that we not put the cart before the horse. Timing of initiation and quality of ART must go together.

    1. I’m just taking you to task for a bit. Really, this is only an argument between those who are saying that we can’t offer the same global standard of care until we do certain things, and those saying we *need* to offer the same global standard of care and therefore *must* do the same certain things. It is about impetus, forward momentum. Believe me, I don’t want anyone harmed… I’ve been thinking about that a lot, writing (for a project) about what sort of patient education materials that will need to be developed to explain when it might be safe for people to start early or not and how all of the factors that you describe will impact on that decision.

  11. That’s fine, but I think our paper would have been ignored or ridiculed if we had used terms like “demand,” “must,” and “need.” We were confining our discussion to the potential harm of treating people early in places where treatment is suboptimal. There’s something that can be done about that concern right now…namely, be aware of the issue and be cautious. Sure, we could have “demanded” that all drugs be made available now, that viral load testing be done every 3-6 months, and that there be no interruption of therapy, regardless of cost and logistics. But that seems a little like “demanding” universal, single-payer health care in the U.S. or “demanding” world peace.

    1. Yeah, I understand that your paper is academic and that I’m talking activism. But I think there is a piece missing if we don’t look back to how we got these programmes off the ground in the first place. Maybe it is just my sense of things, but I feel as though we’ve stalled… particularly when it comes to generic formulations of second, third-line regimens. How best do we secure the next lines of treatment? Is the UNITAID effort going to do enough to deliver cheap POC viral load tests that will work in the periphery… etc…

  12. So, friends, the new guidelines coming out will say TDF and 500 at least. Joel, what your missing is that NOBODY should be initiated on d4T. Of course. There’s been global consensus on that for 2 years. So, then, should countries implement the best guidelines? Yes, they should. And it’s not that hard… take a look at the MSF report and you’ll see that most countries guidelines are keeping pace.

    Speed Up Scale-Up: Strategies, Tools and Policies to Get the Best HIV Treatment to More People

    So the question is not about whether we should implement the best guidelines, your question is really about whether we can–and there’s a reasonable conversation saying that its not possible to provide the standard of care to all people. But if that’s true–if we can’t provide the care that science says is needed, that we EXPECT here in the U.S. then it’s a major crisis and that should be the lead in your editorial.

    All of the concerns you raise are fixable, and in fact fixes are already being implemented. Yes the system is massively imperfect and there’s a clear reason to raise huge alarm bells about failures in the system. What it’s not is a reason to say that there should be a major gap between the standard of care in the north and that in the South.

  13. The two resource-limited countries where I spend the most time are Thailand and Uganda, where there’s plenty of d4T use. In Uganda, no one is started on d4T, but those who were started on it in the past stay on it unless they have overt toxicity (and it has to be pretty overt–no one is doing careful exams for neuropathy or lipoatrophy). In Thailand, as of this February, people were still be started on d4T. WHO Guidelines are just…guidelines, not rules. OF COURSE we’re not providing the U.S. standard of care in resource limited settings. That’s too obvious to need to be stated in our editorial (though we discussed it anyway). Hell, we’re not even providing the U.S. standard of care in many parts of the U.S.!

  14. Right, and you’re not arguing that we should not be structuring programs around ensuring US standards of care in Mississippi right?

    1. Not at all. But in Mississippi, the drugs are available, the lab tests are available, and it’s a matter of getting providers up to speed and getting drugs and treatment paid for. That’s quite different from a place where the drugs don’t exist, the lab tests are unavailable or unaffordable, and the country guidelines still recommend sub-standard therapy.

      1. Of course, if we’re initiating people on old drugs that needs to change. I actually don’t know who this straw-person is who you’re arguing against who thinks people should initiate on d4T at high CD4 counts? It’s certainly not what’s being proposed in any policy space I know about. Instead, as a matter of POLICY we need to both change away from d4T and offer people the opportunity to initiate at higher CD4…

        The argument that some countries have not adopted the current standard of care is not an argument that they should not adopt it, right? So, yes, countries should be advised to move to TDF and raise their initiation threshold, and as they do there should be an global move to eliminate the disparity in the standard of care policy differences ASAP.

        The funding is there–TDF is more cost effective, not less.

  15. Honestly, I think there is a middle path here because we all want to move forward. How do we channel the debate into action? How do we educate the community that what might be safe to do in South Africa, may not be safe to do in Tanzania (where they don’t have a second-line regimen at all)? Can we do it in such a way that we foster more meaningful engagement of PLHIV and the community in the policy making process and in service delivery?

  16. We’re getting pretty far from the point of our editorial, which simply stated that there are ethical issues to be considered when you start expanding treatment to people who have high CD4 counts using sub-optimal therapy. We called for optimization of therapy and monitoring, but argued that until those changes have been implemented, people with early stage HIV infection may be harmed by early ART. No one is specifically arguing for d4T-based therapy in people with high CD4 counts, but if we change guidelines to recommend early treatment, and those guidelines are adopted in places where d4T (or AZT, for that matter) is still used, that’s essentially what will happen. As for how we foster this debate, that was the entire point of the paper. And look…it worked!

  17. But it’s a straw argument… you’re worried countries will fully implement US guidelines of immediate initiation, but do so without implementing any of the other parts of the US standard of care? I just think you’ve got it backward. This should be a rallying cry to expand treatment and quickly move to get systems into shape so that US guidelines can be implemented, which will necessarily mean a move to better regimens, expanded monitoring, more human resources, etc. As a policy question, the fact that its going to be hard on many fronts isn’t a reason to persist in a standard-of-care gap.

    1. Sure.

      I hope you’re right, but countries can easily pick and choose which guidelines they want to follow. For example, in Thailand, they increased the CD4 threshold to 350 but still give d4T. There are other countries that now use TDF but don’t do viral load monitoring. This is no “straw argument.” The idea that countries will suddenly and comprehensively embrace our own standard-of-care, or even WHO guidelines, is unrealistic.

      1. But to your point in the essay, 350 is very far from immediate initiation. I deeply respect your work and your worry and we agree on the priorities of ensuring the capacity to successfully implement US guidelines. But if countries follow your priorities of going slow and instead focusing on a “reduction in dependence on external donor support” then we won’t get there… the focus should be on a strong demand to implementing governments and donors to quickly and fully scale up to a US standard of care and, yes, do so in a way that’s effective and good for patients, not bad.

        1. I agree with you there. I didn’t intend our editorial to be a green-light for “going slow.” We state that early therapy should be a goal and a priority, but not at the expense of patient safety.

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