“I do not raise the memory of Tuskegee lightly, but… the world cannot allow a permanently two-tiered system of global AIDS treatment, with late initiation of outmoded drugs reserved for the South. Nor can we hide behind lack of knowledge or the attitude of `let's wait and see`," said Dr Kevin M. De Cock, the exiting Director of WHO’s HIV Department in the opening plenary address of the 2009 HIV Implementers’ Conference. “Equipoise no longer exists in the debate about early or late initiation, and today's questions are `treat how early?` and `with what?`"
Dr De Cock is a highly esteemed researcher and infectious disease specialist with a longstanding engagement to global health, in particular HIV/AIDS, tuberculosis (TB) and other tropical diseases. He joined the WHO a little over three years ago, after years of working with the US Centers for Disease Control and Prevention (CDC) including six years as Director of the CDC in Kenya. During his tenure at WHO, he is perhaps best known for moving the HIV/TB agenda forward, for launching provider-initiated testing and counselling (PITC) and for the current movement to begin evaluating the effectiveness of universal HIV treatment as HIV prevention.
The man is first and foremost a scientist (his speech began by quoting President Barack Obama as saying “We will restore science to its rightful place and wield technology's wonders to raise health care's quality..."); and word is that this made his term at the highly political WHO a bit rocky at times. Consequently, in the time he has served at WHO, this was perhaps the most candid and powerful speech this reporter has ever heard him make — and it was clearly his swansong as the HIV Department Director. It tackled not only the increasing inequities in global treatment and uncertainties around treatment, but the failures of HIV prevention.
The entire talk and a link to the accompanying slides can be found online here. This article covers some of the highlights and provides more context for some of Dr De Cock’s key points.
Epidemiology
“Despite emphasis on "knowing your epidemic", it remains difficult to answer the simple, essential questions - of the last 1000 infections, in whom did they occur, how were they acquired, where, and from whom?” said Dr De Cock. He noted that modes of transmission vary widely from country to country — within Africa casual sex is the cause of most infections in some countries, but in those countries with the highest burden of HIV, most transmission is occurring within stable relationships.
“The proportion of HIV infections in Africa attributable to male-to-male sex is uncertain,” he said to a mostly African audience, in a country where the previous President (and symbolic father of the country), Sam Nujoma only several years ago had called for purges of gays and lesbians. (“The Republic of Namibia does not allow homosexuality [or] lesbianism here,” Nujoma had said. “Traditional leaders, governors, see to it that there are no criminals, gays and lesbians in your villages and regions.”)
Although the current president, Hifikepunye Pohamba, doesn’t engage in such hate speech, the wounds are still raw, and there appear to be no gay or lesbian venues in the country. Nonetheless, with many Namibian government officials in attendance, including the President and the whole of Namibia’s parliament, Dr De Cock frankly said: “HIV in MSM in Africa not only needs urgent scientific and programmatic attention but should be a priority human rights issue: male-to-male sex is illegal in over half of all African countries, and in four is punishable by death.”
Dr De Cock also pointed out the need to focus prevention efforts on women, especially pregnant women. “Almost 90% of HIV infections in pregnant women are found in just 20 countries, all but one in sub-Saharan Africa,” he said, and he cited recent data from Botswana showing that many women are infected during pregnancy or shortly thereafter. These infections were associated with high transmission rates, and accounted for an estimated total of 43% of all maternal transmissions in the PMTCT programme.
Dr De Cock stressed the high burdens of HIV/TB coinfection. “In 2007, there were about 1.4 million HIV-positive tuberculosis cases, representing 15% of global TB incidence. 26% of global TB deaths were estimated to be HIV-associated, and 23% of HIV deaths were likely from tuberculosis,” he said, stressing that in the high burden countries of southern Africa the burden of coinfection is much greater.
Although the incidence of HIV transmission may have peaked in the last decade, the absolute number of people living with HIV continues to grow — particularly in Africa, which already had a disproportionate burden of HIV. Three million people with HIV in low- and middle- income countries are now receiving antiretroviral therapy (ART).
“However, at the of end of 2007, 6.7 million people were in danger of their lives for lack of treatment, and 23 million were waiting, mostly unknowingly, to become treatment-eligible, sicken or die. With one million people newly on therapy but 2.7 million newly infected in 2007, treatment need continues to escalate. Without substantial reduction in HIV incidence, universal access risks becoming ever more remote,” he said.
Prevention
“Evidence-based prevention interventions are limited in number and efficacy, simple biomedical interventions are lacking, research findings are incompletely implemented, interventions are not targeted,” said Dr De Cock. He noted that “every transmission event concerns two serologically discordant individuals,” and yet fairly little attention has been paid to “prevention with positives.”
Notably, another speaker suggested this could be because of the lack of engagement of people with HIV in designing such a response. Dr Kevin Moody of the Global Network of People Living with HIV (GNP+) said that during a recent technical consultation, people with HIV who were present "felt that the current definition of prevention with positives focuses too much on virus transmission and made people with HIV fully and wholly responsible for HIV prevention. In essence, we were seen as vessels of virus that needed to be contained. Instead, we wanted to see what positive prevention meant to us, our families and communities.”
His group is promoting a new term: "positive health, dignity and prevention," that he feels could help provide for a more enabling policy and legal environment free of stigma and discrimination, a holistic approach to the health of people with HIV (including shared responsibility for HIV prevention), the active participation of most-at-risk groups, and self-determination for people with HIV. “In essence, people with HIV want to be seen as the solution to HIV and not the problem," he concluded.
Dr De Cock said that “for the magnitude of the problem, funding, political will and coverage are insufficient - consider, for example, access to science-based harm reduction for drug injectors or services for sex workers.” He mentioned the new catch phrase ‘combination prevention’ which largely replaced the ‘ABC’ approach at the meeting this year. Combination prevention employs multiple disciplines and approaches, and encompasses individual and small group behavioural interventions, community and structural interventions, HIV testing linked to care, and biomedical interventions.
Dr De Cock then focused on testing. “Universal access is impossible without greatly increased knowledge of HIV status,” he said, and yet around 80% of people with HIV in low or medium-income countries are unaware of their status.
“And there’s been inadequate attention to the prevention benefits of HIV testing,” he said, citing a number of studies showing a reduction in unprotected sex among people who are aware of their status. He noted that in addition to provider-initiated testing and counselling (PITC) (which should be offered to all symptomatic patients; HIV-exposed children or children born to HIV-positive women and men seeking male circumcision for HIV prevention), there are a number of new approaches that could increase testing, including testing of partners and families; mobile and community testing; and door-to-door testing.
“Recently in Kibera - a large slum in Nairobi - home testing was offered to 7,000 people with 96 percent uptake,” he said.
“Research on biomedical interventions to interrupt sexual transmission has been discouraging,” he said noting that of 26 randomised controlled trials of different interventions, 22 failed to show efficacy — the only notable exception being male circumcision. However, earlier this year saw the first encouraging preliminary data from a human microbicide trial for PRO 2000; and preclinical data on topical as well as oral antiretroviral agents (pre-exposure prophylaxis or PREP) seem promising. But even should these approaches prove efficacious, it may be difficult to implement them.
“Assumptions are made about microbicides and women's control - these products are not necessarily that easy to use discreetly, store unobtrusively, or dispose of invisibly, potentially challenging for the most vulnerable. We need to discuss targeting of interventions to where infection incidence is highest - adolescent girls seem to be missed in these trials. Concerning PREP, it may take unusual persuasiveness to convince a decision-maker to give drugs to HIV-uninfected persons when many with declared HIV disease are dying from lack of access,” he said.
He then focused on treatment as prevention, an issue that has recently led to much debate.
“The rationale is clear: transmission only occurs from infected persons; viral load is the major risk factor for all modes of transmission; ART lowers viral load; prevention of mother-to-child transmission offers proof of concept; and there is supportive observational evidence from discordant heterosexual couples,” he said.
He cited a modelling study published last December that found that “in an epidemic of southern African severity, annual, universal voluntary HIV testing followed by immediate ART for those infected would reduce HIV incidence by 95% within a decade, reduce prevalence to below 1% within 50 years, and be cost-saving compared to current treatment scenarios after about 25 years.” He stressed that this paper was not WHO policy, but was meant to stimulate research and discussion.
Treatment guidelines
However it was the subject of HIV treatment guidelines that occasioned Dr de Cock's most forceful remarks.
WHO's HIV treatment guidelines are currently being revised, and Dr De Cock highlighted some of the major questions which need to be considered such as how best to diagnose and monitor, when to start ART, and the optimal nature of first and second-line regimens.
“We have long known of increased mortality in African patients on ART compared with outcomes elsewhere,” he said citing data from Dr Steve Lawn and colleagues showing high rates of death in people with less than 200 CD4 cells and high rates of TB and TB-related death in people with less than 500 CD4 cells. “Although mortality rates at the higher levels may be relatively low, applied to large numbers of people living with HIV, this converts into many absolute deaths… A conclusion would seem that if the future is to be different, we have to intervene earlier, before people with HIV fall into or spend too long in these CD4 danger zones for death and tuberculosis,” he said.
“The question of when to start ART is actually two questions, when to start in relation to acute opportunistic events, and when to start according to CD4 staging. The emerging evidence suggests ART should be initiated as soon as possible in acute [opportunistic] illness,” said Dr De Cock. Likewise, he cited recent data demonstrating that the risk of mortality increases with falling CD4 cells — and that these risks are substantial even at relatively high CD4 cell starting points (for example between 350-500 cells).
“Just on Monday this week, results of an NIH-sponsored randomised controlled trial in Haiti showed that starting ART at CD4+ counts between 200 and 350 yielded substantially better outcomes than deferring treatment till counts dropped below 200,” he said.
The study, CIPRA HT 001, was in over 800 subjects and began in 2005. By the time of a data safety and monitoring board interim review, six people in the early treatment group had died, compared to 23 people in the standard-of-care group— nearly a four-fold difference. Among participants who began the study without tuberculosis (TB) infection, 18 people in the early treatment group developed TB, while 36 people — twice as many — in the standard-of-care group had developed TB. The study was ended immediately, and all the participants were offered treatment.
“Changing starting criteria has major implications for cost and choice of drugs. Starting at a CD4 count of 350/mm3 in countries like Kenya or Zambia will double treatment need,” Dr De Cock said.
He noted that other changes to make treatment more comparable to that in industrialised countries — such as moving away from the drug d4T, which is rarely used in the North, to the easier to tolerate tenofovir, would also cost more money (tenofovir currently costs four times more). (Later in the conference, during a session on pharmacovigilance, angry clinicians yelled at a representative of WHO for the lack of clarity in the current guidance about whether d4T was too toxic to use. “Should we get rid of it or not?” one doctor asked).
Notably, Dr De Cock said that when the current four-drug TB regimen was chosen, “drugs with unacceptable toxicity such as thiacetazone were phased out because collectively we said "Enough, now," even as some argued against change citing cost or drug resistance.”
Expanding ART access for pregnant women, particularly for those who are breastfeeding, is also an issue that needs to be considered in new guidance. However, Dr De Cock pointed out:
“It is tempting to look to revision of guidelines as the answer - but patients don't read guidelines, and guidelines don't build health systems. Late diagnosis and weak maternal and child health services are more important barriers than lack of guidance. PMTCT depends on the same systems that are failing to deliver on MDG 5 — the reduction in maternal mortality — which is highest in Africa, unchanged over the last two decades and one of the greatest disparities in global health. Maternal mortality may be the analogous single most important indicator for the future of AIDS in women and children, perhaps for global health overall,” he said.
The future of universal access and the arc of history
“There is more, a lot more, to AIDS than just technical work,” said Dr De Cock and citing Martin Luther King’s famous quote “the arc of the moral universe is long but it bends towards justice,” he described what should be the philosophical basis for AIDS work.
“If public health is rooted in the science of epidemiology, its philosophic values are equity and social justice. We are entering perilous ethical and political waters, and current practice for poor people of colour in the global South will not be judged well by history if it does not evolve with science and practice in the richer North,” he said.
Dr De Cock then invoked the Tuskegee experiment. He said that others would certainly draw analogies between the current practice of care the world was offering millions of people with HIV in resource-limited settings — failure to diagnose most, and late and sub-optimal treatment to the remainder — and Tuskegee, the most infamous biomedical experiment ever in the US, in which poor African-American men with syphilis were left untreated. It is important to note that this was not so unreasonable when the study began in the 1930’s — the existing treatments at the time were toxic and of dubious benefit — and participants would get them after several months of observation anyway. But soon the money for treatment ran out, and the study continued anyway. In the 1940s, a highly effective treatment, penicillin, became available, but the researchers not only failed to provide treatment, they withheld information about treatment. The study only ended decades later after a whistleblower brought it to the attention of the media — after many men had died, passed the infection on to their wives, and had children with congenital syphilis.
Just like Tuskegee, there is no longer any question that earlier treatment in Africa would save lives — even though how early and the optimal regimen are unclear. But Dr De Cock said that with millions of people in these programmes, the world ought to be able to do research to find the answer — and he proposed conducting a large simple trial with the support of PEPFAR and the Global Fund.
“It is unacceptable, in view of what is at stake - millions of lives, billions of dollars - that despite over 3 million people in the world on ART, we cannot definitively answer the question of when to start treatment. There is ethical as well as medical need for a randomised controlled trial to determine optimal starting criteria in Africa, including assessment of the impact of immediate treatment on tuberculosis incidence. PEPFAR and the Global Fund could resolve these questions once and for all through applied research under field conditions, through a large simple trial, for example, with hard endpoints such as tuberculosis, AIDS, death. Some argue such a study is not needed because we will never have resources to treat more people earlier with better drugs. This is unpersuasive; rationing of health care is a universal reality but let rationing decisions be made transparently, with the involvement of all stakeholders, based on scientific understanding of cost and benefit,” he said.
Ultimately, Dr De Cock believes that HIV treatment should go the way of TB treatment with one, or a few, global, once-daily, first-line regimens containing “the best drugs”
“That it can be done was shown by the tuberculosis community a decade ago. Today, if you get tuberculosis in Jakarta, Kampala or Los Angeles, you receive the same four-drug regimen,” he said.
Doing all this may take “imaginative thinking, renewed advocacy, innovative financing, and more efficient implementation.”
“Global health needs global financing,” Dr De Cock said. “Raymond Biggs, New York Commissioner for Health a century ago, famously said that public health is purchasable and every society can determine its own death rate.”
“Universal access will slip through our fingers unless we reframe it in the broader context of all health-related Millennium Development Goals. From disjointed prevention and treatment of the past we must move towards more intelligent use of ART for treatment as well as prevention, guided by science, stratified by individual serostatus, with all infected persons knowing their rights to health, including sexual and reproductive health. What else is universal access?” he said.
Finally he concluded by quoting Robert Kennedy, ‘Only those who dare to fail greatly can ever achieve greatly.’
“That is the spirit of PEPFAR and the Global Fund. And for all here working on the front lines, far from the halls of power, remember that all public health is local and change is often driven from small places - places that you may not find on any map of the world, but where ordinary people take risks. There is comfort in those other words of Robert Kennedy: `Few will have the greatness to bend history itself; but each of us can work to change a small portion of events, and in the total of all those acts will be written the history of this generation.`
“To which one could add: And so also, one day, will be written the history of this pandemic.”