The State of AIDS at the Barcelona Conference
Inside the biennial International HIV/AIDS Conference there is a forest of speakers and slides on everything from the plight of women in Pune to the ambiguous status of Tat in vitro. This comprehensive conference on the state of AIDS is organized into seven tracks, A through G. The theme of each track is represented in a high-profile plenary speech or two but elaborated in multiple simultaneous slide talks and thousands of individual poster presentations. It's impossible to see everything; with up to ten oral sessions running at once, it's difficult to catch ten percent of what is presented.
Track A is the domain of basic scientific research into the virus and its effects on the immune system. Track B covers the clinical manifestations of HIV disease and the impact of drugs and diagnostics. Track C portrays what we know from epidemiology, where the spread of HIV is tracked into new and familiar populations. Track D considers the range of prevention efforts addressing people both with and without HIV. Track E is a grab bag of social science investigations into issues of underlying social and cultural risk factors for HIV infection, including stigma, and the impact of the disease on families and communities. Tracks F and G focus on efforts to implement prevention, care, treatment and support programs to reduce the impact of AIDS. Track F sticks to the details of undertaking those efforts while Track G explores the political implications and deals with policy and advocacy issues.
The tracks delineate boundaries between specialized bodies of knowledge, but they're really all related. When you select one key from a key chain and hold it up, all the others dangle below. Grasp any fact about HIV/AIDS and you can trace its relationships to a thousand other facts and problems. Drop into a session on Bangladeshi attitudes about marriage and you're only a few conceptual steps from the legal status of widows, the economy of sex work, microbicides and mucosal immunity.
With the number of HIV infections threatening to reach 100 million within five years, the tone of this conference was wary but optimistic. Many attendees noted the emerging consensus to move forward with a dramatic scaling-up of prevention efforts and plans to extend care and treatment to millions of people who have been left behind. A goal announced by the World Health Organization (WHO) to deliver antiretroviral therapy (ART) to three million people in the developing world within the next three years was taken as a kind of "moonshot" challenge. The task will require drawing deeply on the knowledge accumulated by workers in every track of HIV/AIDS studies. But although the commitment is strong, attendees looking for lessons learned by trailblazers found slight guidance.
At the closing session of the conference, in the hours before Nelson Mandela and Bill Clinton spoke, a track-by-track summary of the week's events was presented by a series of distinguished rapporteurs. All of the presentations were excellent (I wish they were included among the webcasts available on the conference site: www.aids2002.com) but one was notable. The final speaker, Terje Anderson, of the U.S. National Association of People with AIDS (NAPWA) reviewed the range of policy and advocacy issues discussed in Track G and focused on persisting inequities. "Without question," Anderson said, "we found here in the sessions and speeches a stronger awareness than ever before that marginalization and stigma continue to shape and define this epidemic." While courts of law have been successfully used to expand access to medications and remove barriers to treatment, he continued, bad law also punishes efforts to teach rational prevention messages and fails to protect the autonomy of people with HIV. "The AIDS movement has become adept at operating within a human rights framework, and using that framework to advance access to treatment, prevention, and ethical research standards. Yet that framework is far from universal."
Anderson also cited the critical leadership role that people living with HIV play in the creation of policy and legislation but warned that, "in order to be real, the meaningful involvement of people living with HIV/AIDS requires real action and commitment, not just ideological lip service." He specifically questioned whether the consensus to treat three million people within three years had really involved input from those it affects most: "How does three million relate to the number of people who need ART. Did anyone ask those who will not receive treatment if they accept this goal as 'consensus'?"
Anderson stressed that the lessons from this meeting must be taken home and implemented: "...this conference clearly showed that, more than ever before, this fight is being fought, and must be fought, on a political plane. That it requires engaged political leadership and that it is our responsibility to engage those leaders when they don't seem to be paying attention the way they must. Yet it remains unclear if scientists, doctors, people living with HIV/AIDS (PLWHA), non-governmental organizations (NGOs), service providers, and other relevant players are truly willing to take the risks associated with entering the political arena. It may be safe to give advocacy speeches and blow whistles among like-minded people at an AIDS conference, but how many are willing to do the same when it could mean loss of government funding, loss of access to decision makers, unemployment, social isolation, or the personal experience of discrimination and stigma?"
What follows is a random walk through a handful of oral sessions at the conference, track by track, from political interventions to protein interactions.
Track F: Interventions
The use of single dose nevirapine to prevent mother-to-child transmission (MTCT) of HIV has been proven safe, effective and appropriate in situations where minimal pre-natal care is available. But programs have encountered reluctance on the part of some women to accept voluntary counseling and testing (VCT) without the consent of their husbands. An antenatal VCT program in Lusaka, Zambia encouraged women to bring their spouses for testing, but there was little response. Active strategies were designed to raise awareness among men in the community about HIV and VCT and engage husbands in a discussion about HIV testing. Among these:
The result was a dramatic increase in the number of couples receiving VCT. Uptake of testing among men attending counseling was 92%; HIV prevalence was 34%. The authors conclude that "Couples counseling may help facilitate better uptake of interventions to prevent transmission to children and is more likely to be effective to support primary prevention of HIV transmission." (E. Shutes, MoOrF1032)
Track E: Social Sciences
An analysis of interviews with men and women living in the slums of Chennai revealed the depth with which violence to women is embedded in the culture. Most respondents held that men typically beat their wives as a normal part of married life. "Women described being slapped, kicked, having their head hit against the floor and being burned with lit cigarettes; some were struck with objects such as ladles or stones. Slapping or hitting the face was the most frequent type of violence and physical consequences such as recurring headaches and blurred vision were noted." But although wife beating was accepted as the social norm, there was discordance between men and women as to the acceptable limits of the violence. The authors conclude that in this culture, if a woman wishes to minimize violence, her ability "to insist on monogamy, negotiate condom use or refuse sex is limited." Therefore, within this context where violence is a gender norm, prevention messages that target men are likely to be most productive. (V.F. Go, Johns Hopkins; WeOrE1284)
Globally, 30 percent of people infected with HIV are between ages 15 and 24, and over half of new infections occur in this group. Young women are particularly at risk because they lack economic resources of their own and often become dependent on men. Some prevention programs aimed at youth tend to treat young people as a problem and ignore conditions that leave them vulnerable. A program in Nigeria tried an integrated approach to reach adolescent girls and young women and address the underlying issues that make them more vulnerable to HIV. The integrated approach views youth as a resource and seeks to make them participants rather than audience members. A training manual was designed that combined sexuality education and entrepreneurial education. The training sessions demanded about four hours a week and ran for about six months. When trainees completed the course they became qualified as peer counselors in HIV/AIDS and reproductive health.
Girls who wrote business plans were also given vocational training in fields such as hairdressing, fashion design and tie-dye, and offered microfinancing (about $150) to begin small businesses. This program in Oyo state sought to train 1,000 girls; 303 young women completed training in reproductive health and entrepreneurial skills. Of these, 73 women wrote business plans and 34 were supported with financing. As peer educators, the girls subsequently provided sexual health counseling to about 65,000 young people. The program reported that when young people were given the skills and backing to start their own business they gained in self-esteem and independence. Girls with enhanced self worth were better able to make informed decisions and contribute to their community's development. "Economic independence helped to reduce vulnerability to sexually transmitted diseases (STDs) including HIV/AIDS." (F. Olatidoye, MoOrE1026)
Track D: Prevention
A randomized trial was conducted in STD clinics in three cities in the United States to compare conventional HIV testing employing two counseling sessions one to two weeks apart, to rapid HIV testing employing two sessions delivered on the same day. The two outcomes of interest were the number of test results received by clients and the incidence of STDs during the subsequent year. The investigators enrolled 3293 individuals who were interviewed and screened for chlamydia, gonorrhea, and trichomoniasis at baseline and again every three months for one year. Participants were tested for HIV and syphilis at baseline and again at 12 months. Roughly half of the participants were female; ages ranged from 15 to 39 years.
Nearly all (>95%) participants given a rapid HIV test received their results, while only 68% of those who were given a conventional test returned to learn the outcome. However, significantly more people who received the rapid test were diagnosed with a new STD at six months than those who had the conventional test with two counseling sessions (22% versus 12.6%, p= .04). However, by 12 months this gap had narrowed and was no longer statistically significant (18.8% versus 16.9%, p= .14).
Several rapid HIV tests are moving towards FDA approval in the U.S. pressed by the recognized need to reach significant numbers of people who fail to return for conventional test results. This is an important study because it assesses whether good-quality risk-reduction counseling given in a single clinic visit can be as effective at preventing STDs and reducing risky behavior as conventional counseling delivered over two successive clinic visits. (C.A. Metcalf, MoOrD1019)
A study in Nairobi, Kenya looked at how people typically sought care for STDs in that city and what kind of advice and treatment they received. A previous program had trained 600 qualified providers in syndromic diagnosis and treatment of STDs. Surveys in homes, streets and markets assessed how frequent STDs were and recorded how they were treated and by whom. The providers were then visited to establish whether they had received training or not.
About 15% of the adults contacted in the survey reported having an STD in the past year. "Of these, 25% did nothing; 10% went directly to a medicine shop; and 65% sought treatment. Of those who sought treatment, 44% went to a government clinic; 39% to an untrained private provider, and only 17% to a trained private provider."
Neighborhood medicine shops are a frequent source of advice and treatment for STDS. As part of the study, a number of these shops were visited by young men and women who acted as undercover "mystery shoppers." Half of them described symptoms of common STDs and half presented a prescription to be filled. Of the male mystery shoppers who described symptoms of syphilis, only 1 in 18 were given the correct medication and 5 of 27 males describing gonorrhea were correctly treated. Of females, only 1 in 11 of those presenting syphilis and 1 of 20 describing gonorrhea were correctly treated. In larger medicine shops, only 63% of prescriptions were filled due to unavailability of the drugs.
The authors conclude that, "Training 600 private providers was a good start, but to improve coverage either these trained providers must be more actively marketed to STD patients, or training must be extended to unqualified providers. Medicine shop staff are really bad at diagnosing STDs. They should be trained to refer." (C. Nkatha, TuOrD1154)
Track C: Epidemiology
At the Durban conference in 2000, there was much evidence that circumcision, especially if performed early in life, is a protective factor for acquiring HIV. The biological rationale is that the mucosa of the glans penis in circumcised men becomes keratinized and resistant to irritation and infections. But previous studies compared men from different communities with possibly different sexual behaviors. For example, low rates of HIV among North African Islamic men may be attributed to circumcision, the practice of washing before and after sex, or the practice of keeping multiple partners within closed sexual networks. These confounding factors make conclusions uncertain.
To minimize the effect of cross-cultural practices, Kawango Agot and colleagues performed a study to assess the prevalence of HIV among culturally homogenous circumcised and uncircumcised men in the Luo ethnic community in rural Kenya. The men selected were members of an African instituted church congregation, were all sexually active, and ranged in age from 18 to 59. Of 1,217 men contacted, 845 agreed to be tested for HIV and have their circumcision status confirmed.
The seroprevalence of HIV-1 was 30.2% among 447 uncircumcised men and 19.8% among 398 circumcised men. Uncircumcised men (who did not use condoms) were at greater risk for having HIV independently of other demographic or sexual behavioral factors.
This cross sectional study supports the biological rationale for the protective effect of circumcision. A randomized, controlled, treatment trial comparing circumcision plus risk reduction counseling to counseling alone is underway. (K. Agot, ThOrC1486)
French researchers examined a large cohort of HIV seroconvertors to see if the rate of progression to AIDS differed between men and women. The study considered both the "natural course" of infection in 424 individuals (94 women, 22%) observed for a median of 75 months before the advent of HAART in 1996, and in 531 individuals (167 women, 31%) who started HAART while in the cohort and had been followed for a median of 37 months. The effects of gender were evaluated in the pre-HAART group by time since infection to clinical AIDS, to CD4 count under 200, and to death. The post-HAART group was tracked for changes in CD4 count and viral load since starting HAART and for time to an AIDS defining event.
Men and women enrolling in the pre-HAART group were similar as to age (28 vs. 31 years), CD4 count (569 vs. 688) and viral load (4.1 vs. 3.7 log). "Progression to AIDS was lower in women (RR=0.4, p<0.01). This benefit persisted after adjustment for age, baseline CD4 and VL (RR=0.5, p<0.04)."
At the time of starting therapy in the post-HAART group, men and women had nearly identical CD4 counts (247 vs. 246) and viral load (4.2 vs. 4.1 log). After 12 months on HAART, men and women experienced similar increases in CD4 count (86 versus 102) and decreases in VL (1.2 vs. 0.9 log). "Adjustment for age, CD4 and VL at HAART initiation, and prior use of ART did not modify this result."
The authors did not find evidence that women with similar viral load to men progress to AIDS at a more rapid rate in either the natural course of disease or after initiating HAART. (J.B. Hubert, ThOrC1448)
Track B: Clinical science
One vexing problem facing efforts to scale up treatment in the developing world has been the lack of basic infrastructure such as transportation and refrigeration. In particular, diagnostic assays have been designed and validated under conditions where rapid and safe transport to laboratories is common. One proposed solution to the problem of safely transporting tubes of blood is to collect samples as dried blood spots on filter paper.
A Thai group performed a validation test of dried blood spots by collecting whole blood, plasma and spots and processing them in parallel. Samples were tested for both HIV RNA and DNA detection and for HIV RNA viral load. The investigators also collected spots and stored them at a range of temperatures for periods up to one year, then tested them for reproducibility of viral load.
In the series of stored samples, dried blood spot viral load results were reproducible within 0.5 log at copy numbers above 10,000 out to three months. The other tests were qualitatively comparable to the reference tests. The authors conclude that dried blood spots are reliable and stable for HIV detection and viral load analysis. (T. Chaowanachan, WeOrB1339)
A latebreaker report on ACTG 384 may be the stand out of the conference. This was a complicated, multifactorial trial conducted by the U.S. AIDS Clinical Trials Group. In a nutshell, the study convincingly shows that beginning therapy with efavirenz/AZT/3TC is better than starting with nelfinavir/ddI/d4T. These assumptions were already reflected in the British HIV Guidelines but have been slow to be embraced in the U.S. This study may have a big impact on the guidelines for selecting simplified regimens for use in low resource settings. Interestingly, seven years after the protease inhibitor revolution, the best first line therapy has turned out to be a one-target strategy, with PIs now a second line choice.
Track A: Basic Science
This track offered a full program of talks and posters, yet little that was memorable. Most scientists now reserve their important presentations for the annual Retrovirus conference held in the U.S. each winter. The International AIDS Society (IAS) last year began another biennial conference, held in the years between the large International Conferences, that they hope will develop into an important basic science meeting. So far the Retrovirus conference is safe on its perch, but the new IAS meeting has the potential to become an important catalyst for accelerating the scale-up of treatment and care projects.
On the immunology front, one development with important implications is the growing body of evidence that HIV can mutate to escape from immune control in a way that is analogous to escape from drug pressure. At this meeting, more people got their first look at evidence that the virus can escape from suppressive control by cytotoxic lymphocytes (CTL). Bruce Walker reported on an individual who had successfully been able to control replication of his virus without treatment then experienced a sudden surge in viral load. Sequence analysis of the individual's virus revealed that he had been infected with a new viral strain that his immune system no longer recognized. This may be the first documented case of super-infection; if it is a common phenomenon, this news does not bode well for current vaccine strategies that try to elicit suppression by CTL.
In another report of super-infection, Stephanie Jost of the University of Geneva described the case of a male participant in a European clinical trial with documented subtype AE HIV who experienced a viral load spike during a planned treatment interruption. Sequence analysis of the virus dominant at the time of the spike was documented as subtype B. Co-infection was ruled out by failing to find any evidence of subtype B virus in earlier stored samples. This particular strain of subtype B virus is associated with strains found in Brazil. Three weeks before the patient's viremic episode, he had vacationed in Brazil where he reported having several unprotected sexual contacts. (S. Jost, ThOrA1381)
There was data on viral escape from host cytotoxic lymphocytes (CTL) in monkeys presented by David O'Conner from the Wisconsin Regional Primate Center. This group showed that during acute infection, epitopes in the SIV genome that tend to stimulate the first wave of strong CTL immune responses were also the first to mutate in the functional virus. These mutations ultimately allow SIV to escape the body's alien detection and removal system. CTL responses that arise later, during the chronic phase, are less likely to escape but are also less able to control infection. He also reported that acute phase mutations occurred throughout the viral genome, involving more than just the few key epitopes. The group also speculates that the rapid pace of mutation observed during acute phase may be responsible for generating the tremendous diversity of viral variants seen circulating in populations. (D. O'Conner, TuOrA1179)
For diehard fans of virology, a session on the role of the "accessory" proteins was notable. Warner Greene from the Gladstone Institute in San Francisco took a shot at the session's title. "There are no 'accessory' proteins," he said, "they are all essential." He also commented that with integrase inhibitors on the horizon, we have run out of viral enzymes as therapeutic targets and are now beginning to explore interfering with protein-protein interactions. He cited the entry inhibitor T-20 as the first example of this kind of therapeutic.
Tat is an essential accessory protein that was recognized early on as giving a big boost to the ability of HIV to replicate. When an infected cell starts to make new copies of HIV, Tat is one of the first proteins summoned. Without Tat, the cell's genetic machinery can transcribe copies of HIV, but it is a slow process. Once Tat is on the scene, the machinery kicks into high gear, transcribing the HIV genes thousands of times faster than before. But it seems that Tat can't help being helpful and several new functions of Tat are now being recognized.
Mark Wainberg elaborated news about Tat that he presented at the Retrovirus Conference earlier this year. He suggests that Tat may have a dual nature depending where it finds itself during the viral lifecycle. At a later stage, when new virions are being assembled and packaged, TAT may help suppress the reverse transcriptase protein to keep it from transcribing the viral RNA at an inappropriate time. This ability to suppress DNA elongation seems to be located in the second exon of the tat gene (see below). But two other functions of Tat (associated with the first exon) actually help reverse transcription take place by facilitating the placement of new nucleotides on the growing DNA chain. So depending on the situation, Tat can either help or suppress RT activity. Interestingly, the helping functions are also performed by a completely different protein, so Tat seems to serve as a backup. This dual nature illustrates the complexity of protein interactions in the HIV life cycle and suggests how much more basic research needs to be done. (M. Wainberg, WeOrA1259)
Kuan-The Jeang zeroed in on some quirky observations about the Tat protein. There are two coding regions on the tat gene of HIV and SIV; together they code for the tat gene product, which is necessary to make a fully virulent virion. But Jeang presented data suggesting that a tat gene that only expresses the first exon but not the second is less stable, hence less virulent and maybe associated with milder disease. (Exons are the regions of a gene that directly code for a protein; expression is the process of turning of an exon into a protein.) While this has been observed in test tube experiments with cells, such data is never as compelling as data from living creatures. Jeang crafted a modified SIV (monkey virus) that only expressed the first exon of tat. The virus was engineered with a stop codon placed just before the second exon begins. He then infected four rhesus monkeys with this artificial virus (tat1ex) and two monkeys with the unmodified two-exon tat virus (tat2ex). The monkeys that received the two-exon virus quickly developed high viral loads and had a progressive course of disease. But the four monkeys infected with one-exon virus maintained low or undetectable viral loads during the first few months after infection. Eventually, two of these monkeys took a turn for the worse. Sequencing the tat region of their viruses revealed that the stop codon preventing the second exon from being expressed had mutated to allow the full Tat to be made. The evolutionary switch of this one signal allowed normal disease progression to occur.
Monkey experiments are interesting but far less convincing than studies in people. Of course, this study would be impossible to perform in humans. But remarkably, Jeang discovered "an experiment in nature" that supported his observations in the monkeys. It seems that, between 1985 and 1990, three laboratory workers were accidentally infected with a special investigational strain of HIV (HXB2) that had a blocked second exon in tat. Here was an experiment that could never be carried out deliberately. Jeang reviewed the medical histories of the three individuals -- all still living -- and sequenced their virus from stored samples. Two of the lab workers have had a rather uneventful course of disease with only modest T-cell declines after all these years. The third individual has had a more variable history with periods of stability and other periods of high viremia and T-cell loss. The gene sequence data showed that his periods of disease progression were correlated with a mutation at the stop codon in the tat gene that unblocked the second exon. The sequencing data showed that the other two individuals never experienced an unblocked second exon.
This is a small, but convincing demonstration of the theory that a blocked second exon of the tat gene is associated with a milder course of disease. It also raises the question of whether a therapy that restricted this gene or its product could lessen the impact of an existing infection. (K.T. Jeang, WeOrA1256)
This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.