The extensive spread of HIV started late in Asia, compared with the rest of the world. The earliest cases of AIDS were reported from Asia in 1984 and 1985,1 but the potential for widespread epidemics was not appreciated until the more extensive spread of HIV in Cambodia, India, Burma, and Thailand in the early 1990s.2, 3, 4 Unfortunately, the lessons of devastation from AIDS in Africa and the Caribbean went unheeded in much of Asia, and success stories of disease prevention at the national level in the region remain few. This review will highlight the current extent and features of Asian epidemics, discuss growing care needs and the clinical presentations and treatment of HIV in Asia, and briefly discuss a few prevention and care successes in the region to encourage more aggressive action to contain national epidemics and provide appropriate care for the people of Asia.
Search strategy
A complete search was made of MEDLINE, PsychInfo and POPLINE for HIV or AIDS and the term Asia or the name of any Asian country. These citations were then loaded into Endnote and a search was made on key epidemiological and behavioral terms (prevalence, surveillance, condom use, MSM, sex worker, etc) to extract relevant articles. Similarly, in preparing sections on treatment and opportunistic infections, searches were made on terms such as antiretroviral, tuberculosis, opportunistic infection, and so on. The section on responses drew more heavily on the authors' experiences and published descriptions of responses, as little of this material has made its way into the peer-reviewed literature for Asia. The number of references used had to be pared substantially given the reference limits. A number of additional external reports known to the authors were used, especially for behavioral surveillance data and national modelling work, which have not appeared in the peer-reviewed literature, although they have been carefully reviewed by national programmes and national advisory groups on modelling. For HIV surveillance data, much of the information was drawn from the HIV Surveillance database maintained by the US Bureau of the Census or from unpublished reports of surveillance data where we had permission to use them or they were presented at conferences or national dissemination meetings.
As in many other areas, Asia shows extreme diversity in its HIV epidemics, both geographically and temporally. figure 1 shows the geographic distribution of HIV in the region. National adult HIV prevalence varies from near 0% in several countries to almost 3% in Cambodia.5 But a static map cannot show the time evolution of these epidemics—and therein lie major hints about the future of HIV in the region. Temporally, the countries of Asia can be divided into three categories: (1) those where HIV hit early and hard, and where adult HIV prevalence now exceeds 1%—eg, Cambodia, Burma, Thailand, and some states in India; (2) those currently in transition, with HIV epidemics growing noticeably in the past 5 years—eg, China, Indonesia, Nepal, and Vietnam; and (3) those having very low levels of infection such as: Bangladesh, Laos, the Philippines, and South Korea.
That HIV epidemics in Asia have been driven largely by sex work and injecting drug use is well established.3, 6, 7, 8, 9, 10 In Asia, they typically follow a chain of transmission, as outlined by Weniger and colleagues.9 In most places HIV spreads first among injecting drug users, followed by HIV spread among sex workers. Clients of sex workers are the next link in the chain, and they then transmit the virus to their female sexual partners. Most women infected in Asia have been the monogamous wives or regular partners of higher risk men.11, 12 HIV in children, through maternal infection, represents the final link in the chain.
Moreover, it is becoming clear that men who have sex with men are also contributing substantially to Asian epidemics, although they have been neglected for many years in the response to HIV.13 Early reported AIDS and HIV cases in many places in the mid to late 1980s were dominated by men who have sex with men, although the trend shifted in the 1990s to heterosexual transmission.14, 15 In several Asian countries, men who have sex with men continue to play an important part in reported HIV infections—for example, 23% of reported infections in the Philippines up to the end of January, 2004, are attributed to such men (Philippine HIV/AIDS registry), 21% of cases in Korea during the late 1990s were in men who have sex with men,16 and newly reported infections among such men overtook heterosexual infections in Japan again in 1999 (Japanese surveillance data). These data are now being lent support by results of sero-epidemiological studies. Systematic sampling in Bangkok, Jakarta, and Phnom Penh have shown HIV infection rates of between 2·5% and 22% in men who have sex with men.17, 18 Behavioural studies around Southeast Asia further verify high risk behaviour among many such men: in Vietnam, only 40% of men having anal sex used a condom at last sexual intercourse;19 in Beijing, 49% reported unprotected anal intercourse in the previous 6 months;20 and only 12% of waria (male-to-female transgender) in Indonesia reported consistent condom use in any sex act.21
Figure 2 shows the evolution of HIV prevalence in several surveillance sites from countries around the region in female sex workers and injecting drug users. The early and fast growth of the sex work epidemic in Cambodia, parts of India, and Thailand is apparent, whereas those in China, Indonesia, and Vietnam have been substantially delayed and grown more slowly. The epidemic in Bangladesh and the Philippines remains low even now, but recent rises in numbers of injecting drug users in Bangladesh are worrying.
National HIV epidemics in Asia are composed of many smaller geographically diverse epidemics such as those shown in figure 2, but the large size of many Asian countries, limitations in coverage, and changes over time in surveillance systems often make it difficult to clearly ascertain the overall national situation. For example, in both India and Burma, national surveillance systems include only two sites for sex workers, both in large urban centres, making it difficult to understand what is happening on a national basis. Even within countries substantial variability exists in timing and rate of epidemic growth in at-risk populations. In Yunnan, China, the epidemic among injecting drug users underwent rapid growth in the late 1980s,22 but in Guangdong this only took place in the late 1990s.23 In Vietnam, the quick rise of HIV in sex workers in Ho Chi Minh City and Hanoi began in 1997 and 1998 reaching 24% and 15%, respectively by 2002, whereas national rates have grown much more gradually but steadily to more than 5%.24, 25 But in each case, even if it is happening more slowly than in countries such as Thailand and Cambodia, the chain of transmission is the same, and prevalence of infection in pregnant women in Vietnam tripled from 0·09% in 1998 to 0·28% in 2002.25
Since the chain of transmission is generally the same, what are the reasons for this wide variation in the speed of evolution and severity of Asian epidemics? Several factors certainly contribute, including: (1) variations in behavioural factors—eg, the levels of risk behaviour, the frequency of sexual and needle-sharing behaviours, adoption of preventive measures, and variations in the linkage among different at-risk populations across the countries of Asia;26 (2) geographic and population differences in biological factors including the efficiency of different transmission modes, levels of other HIV-facilitating sexually transmitted infections, and circumcision;27, 28 and (3) the timing of HIV introduction into populations with high behavioural risk.
The range of variation in these behavioural and biological factors between and within countries can be quite large. For example, the percentage of adult men visiting sex workers in the past year as seen in large-scale surveys varies from 5% in Hong Kong29 to 9% in China30 to 22% in Thailand31 (later reduced to 10% in response to the HIV epidemic).32 Consistent condom use between direct sex workers and clients, measured by behavioural surveillance, varies widely from lows of 2–3% in Bangladesh to almost 90% in Cambodia (Bangladesh and Cambodia Behavioral Surveillance). And as behavioural surveillance data around the region show, these values are changing over time.26, 33 But they remain low in many countries in the region including China, Indonesia, and the Philippines. Assessing the HIV potential in every country of Asia needs careful consideration of the combined effect of these various behavioural and biological factors.
Chin and colleagues34 proposed that the most important of these factors determining the severity of Asian epidemics were the size of the adult male population visiting sex workers and the numbers of sex workers' clients per night. To test this hypothesis, Brown and Peerapatanapokin35 developed a model that incorporated all of the key factors outlined earlier.36 Based on a careful analysis of these factors, specific models, taking into account all these factors, were prepared for both Thailand and Cambodia. Starting from observed behavioural trends, these models accurately reproduced 10 years of HIV prevalence trends in the key populations in both countries.37, 38 This model has been used here to assess the effect of client population size and frequency of commercial sex on the timing and severity of Asian epidemics under the behavioural and epidemiological conditions prevailing in the region.
Taking into account the introduction of HIV in 1985, with condom use at last commercial sexual intercourse remaining at the 30% level from 1990 onwards, the results of varying the size of the client population are shown in figure 3. Countries such as Thailand and Cambodia, where 20% of adult males were visiting sex workers in the early 1990s,31, 37 would see the epidemic take off rapidly in the late 1980s or early 1990s and rise to 15% adult prevalence levels. Other countries such as China or Vietnam, where only 5–10% of men visit sex workers, would not see the epidemic happen until the mid or late 2000s and rise to 3–7% levels in the absence of interventions. Thus, it is not surprising that sex work epidemics in these countries only seem to be growing now. Epidemics in injecting drug users can accelerate the growth of this sex work component of the epidemic if these drug users are clients of sex workers, producing even earlier epidemics in sex workers and clients.36 Behavioural data from around the regions shows that a substantial proportion of injecting drug users are clients of sex workers.26
Why then did Thailand and Cambodia not reach HIV prevalences of 15%? The reason is that they undertook extensive and intensive prevention campaigns with good coverage, which were focused specifically on reducing risk related to sex work in both clients and sex workers. In both countries, condom use between sex workers and clients increased to more than 90%, and the number of men visiting sex workers was halved (from 20% to 10%).32, 37, 38, 39, 40, 41 As a consequence, adult HIV prevalence peaked at roughly 1·5% in Thailand in 1996 and at 3·3% in Cambodia in 1998. Prevalence is currently falling in both countries, rather than continuing a steady growth to 15% levels. Modelling data in both countries has shown that these prevalence declines are almost entirely linked to the behavioural changes described above.37, 38
This result then raises the issue of what is likely to happen in the countries in transition such as China, Indonesia, and Vietnam. In the absence of extensive prevention programmes to reduce HIV transmission in at-risk populations (clients and sex workers, injecting drug users, and men who have sex with men), they might be expected to see steadily climbing HIV prevalence, as in the lower curve of figure 3. In China and Indonesia, consistent condom use between sex workers and clients is essentially steady at 10% to 20% (national behavioural surveillance results), with no substantial increases over the past decade. And in all three countries, surveillance data show continuing epidemics of injecting drug users and growing sex work epidemics in several places.
And what of the countries that still have low prevalence of HIV? Some might continue to have little HIV spread. As figure 3 shows, if a country has only 5% of men visiting sex workers and no epidemic of injecting drug users, prevalence could remain quite low for a long period. But such assumptions about the future should be made with extreme caution. In many countries, knowledge of sex work and injecting risk is poor or is based on small, non-representative samples that are not generalisable. Behaviour might change with time, and an injecting drug population might develop in the future. And in some countries with pockets of high risk, such as Bangladesh, HIV might have only recently have gained a foothold. HIV surveillance in Bangladesh has now detected 4% prevalence in injecting drug users in one site that injecting drug users heavily visit sex workers (40% in the previous month in that site), and the data show many sex workers have four to seven clients per night.42 That this will remain a low prevalence country is not at all clear.
Unfortunately, the prevention successes of Cambodia and Thailand are not being well replicated in the other countries in Asia. Although there has been some progress, condom use in sex work remains low in many places, coverage of current prevention programmes for at-risk populations is very low (and few data are available for coverage), and low priority is accorded to HIV prevention because prevalence is currently low. Although what works in prevention in low prevalence settings is well known,43, 44, 45, 46 measures are not being taken.
Failure to undertake early prevention programmes will have financial consequences for countries, especially as the world enters an era in which highly active antiretroviral treatment (HAART) is judged to be a right for people living with HIV. Currently, WHO estimates that 1·1 million Asians are in need of HAART, with only 6–7% having access.47 table 1 shows the financial consequences for the five countries with the largest numbers of HIV infections in Asia. If one assumes that 20% of these populations need to be treated with the original brand name NNRTI (non-nucleoside reverse transcriptase inhibitor)-based HAART, the estimated antiretroviral (ARV) cost per year for Thailand and India will be US$241 million and US$1·43 billion, respectively. And yet, most Asian countries are judged to have intermediate income by the World Bank and are thus not eligible for at-cost prices for ARVs from many pharmaceutical companies. Recent progress has been made through production of generics in China, India, and Thailand—eg, the fixed dose combination of stavudine, lamivudine, and nevirapine, which has proven effective.48, 49, 50 However, good quality assurance programmes, such as that being developed by the Thai Red Cross AIDS Research Centre (TRC-ARC) HIV-NAT (Netherlands, Australia, Thailand) collaboration (pharmacokinetic laboratory), must accompany the development and manufacture of generics.51, 52, 53
ARV availability varies greatly from country to country. In some, such as Japan and Hong Kong, broad access to ARVs and quality medical management is available. Thailand plans to provide access to 50000 people in 2004, with a goal of universal access for those in need. Yet, in the larger countries of Asia, such as India, Indonesia, and China, access remains very restricted, and current programmes are hindered by serious management problems, sometimes leading patients to abandon treatment.54, 55 Providing Access for All will thus remain a significant challenge for the foreseeable future.
Three major HIV–1 subtypes are dominant in Asia: C, CRF_01AE, and B.56 Subtype C, the most globally prevalent subtype, is the most common form in India.57 In southeast Asian countries such as Thailand, Cambodia, Burma, and Vietnam, the circulating recombinant form: CRF_01AE dominates, although subtypes B' and C are fairly common.58, 59, 60, 61 Subtype B predominates in Japan, Taiwan, and the Philippines, although CRF_01AE has recently became more prevalent in the Philippines.58, 62, 63, 64, 65 In China, diverse HIV-1 strains have been identified. Subtype B, C, CRF01_AE, and CRF08_BC are circulating in individuals who acquired HIV infection sexually, whereas subtypes CRF08_BC (more than 80%) and CRF07_BC have been detected in injecting drug users.66, 67 But in the HIV epidemic in paid blood donors in Henan and Hubei provinces, HIV-1 subtype B' is most common.68 Active recombination is underway in the region, and new forms of HIV-1 intersubtype C/B' and C/B'/E recombinants with different recombination breakpoints have recently been reported from central Burma61 and from China.66, 69 These findings represent the complex diversity of HIV epidemics in the region. Molecular epidemiology has also proven useful for mapping HIV spread along heroin routes, with different trading routes mapping to different mixes of subtypes.10 The diversity of mixing recorded in heroin routes crossing the countries of southeast Asia indicates that any one country's narcotics and HIV programmes are unlikely to succeed unless the regional narcotic-based economy is addressed.
Targeting of prevention efforts will improve if new technologies can be applied to assess incidence. In the past few years, several new technologies have been developed to measure recent infections in cross-sectional samples.70, 71, 72 The dual enzyme immunoassay (EIA) testing strategy using a standard high sensitivity HIV EIA and a less sensitive EIA has been used to identify people who seroconverted, on average, within the past 129 days.73 Studies have shown that the sensitive with less sensitive (detuned) anti-HIV testing strategy provides accurate diagnosis of early HIV-1 infection, provides accurate estimates of its incidence, can facilitate clinical studies of early infection, and provides information on infection duration for planning care.73, 74, 75 However, difficulties still exist in calibrating these approaches for use on non-B subtypes, which dominate in much of Asia. New approaches, such as an IgG capture BED enzyme immunoassay that might prove more effective for non-B subtypes, are being developed and have now been tested in groups in both Thailand and Cambodia.76 Further calibration of these approaches and research into their application for the subtype mixes seen in Asia is needed.
Variations in host genetics might also play a part in the spread of HIV, resistance to infection, or progression to disease in Asia. Polymorphic allelic variants of chemokine receptors CCR2 and CCR5 and of stromal-derived factor-1 (SDF-1), the ligand for the chemokine receptor CXCR4, are known to have protective effects against HIV-1 infection and to be associated with delays in disease progression. Few data have been generated from Asian populations for these issues, but the CCR5δ 32 allele is rare in Asia.77, 78 A Thai cohort study of highly exposed, but persistently seronegative (HEPS) women suggests that homozygous CCR2b-64I might be one of the factors mediating resistance to HIV 1 infection.79 The CCR2b-64I allele prevalence varies from 3% to 17%.77, 78 Homozygous SDF-1 3' A gene has been reported among Asian populations at a rate of 8–13%.78, 80 In a study of exposed but uninfected injecting drug users in Vietnam, reduced susceptibility of peripheral blood mononuclear cells to HIV-1 infection was associated with resistance to infection in these individuals.81 In nine uninfected Chinese in Taiwan, with histories of multiple sexual exposures to HIV, macrophage inflammatory protein (MIP)-1α, and MIP-1β, but not interleukin 16, were detected significantly more frequently than in controls.82 Further studies of these and other host factors related to resistance to HIV-1 infection and delay in disease progression among Asian populations are warranted.
The natural history of HIV in Asia varies from what has been seen in other parts of the world. In Asia, progression from HIV infection to AIDS is faster than in the West: 6·9 years in a Thai cohort83 and 7·9 years in an Indian study,84 compared with 10 years or more in most pre-HAART western cohorts.85 In the developing countries of Asia, the three most common opportunistic infections are tuberculosis (mostly extrapulmonary), cryptococcosis, and Pneumocystis carinii pneumonia.86, 87 Disseminated Penicillium marneffei also occurs with some frequency in southeast Asia (northern Thailand,88 southern China,88 and northeastern India89); and treatment with amphotericin B followed by itraconazole is recommended and judged to be cost-effective.90 Mycobacterium avium complex disease is seen more commonly than previously thought. Up to 30% of HIV infected patients with chronic fever or weight loss, or both, in Thailand were found positive for Mycobacterium avium complex,91 and in Taiwan, patients with this disease had shorter survival than those with disseminated tuberculosis.92 However, in developed Asian countries such as Singapore and Taiwan, P carinii pneumonia, not tuberculosis, is the most common opportunistic infection in advanced disease.93 Of 309 cases reported from Taiwan, the five leading HIV-associated opportunistic infections included oro-oesophageal candidosis (63%), P carinii pneumonia (30%), tuberculosis (25%), mucocutaneous herpes simplex infection (24%), and cytomegalovirus diseases (24%).93
A few studies have looked at HIV and co-infection with hepatitis B (HBV) or hepatitis C virus (HCV) in Asia. Workers in Singapore94 noted 8·5% HBV-HIV co-infection, with those with HIV three times more likely to be HBV infected than controls. Studies in injecting drug users in southern China showed that baseline anti-HIV and anti-HCV positivity was high (17% and 72%, respectively) and that HCV seroconversion took place at a rate of 37·6 per 100 person-years in HCV-negative individuals.95 Another study in southeastern China recorded HCV co-infection in 99·3% of HIV-positive injecting drug users.96 These investigations show that rapid HCV spread among injecting drug users is running parallel to HIV spread, and that physicians should be prepared to treat co-infections. In commercial vehicle drivers and STD patients in India, high rates of HBsAg positivity have been seen, and in one study, a quarter of those HBsAg positive were HIV co-infected.97, 98, 99 A Thai study with co-infection rates for HIV and HBV, HCV, or HBV/HCV of 8·7%, 7·2%, and 0·4%, respectively, found that co-infection was a major predictor of severe hepatotoxicity on initiation of antiretrovirals.100 This finding shows the importance of training Asian physicians to test for and properly manage HBV/HCV/HIV co-infection.
The strong association of tuberculosis and HIV in Asia both increases tuberculosis incidence and raises treatment issues as the region enters the HAART era.101 Rifampicin reduces plasma levels of non-nucleoside reverse transcriptase inhibitors (NNRTI), a mainstay of triple combination HAART, up to 31%.102 Accordingly, recent treatment guidelines have recommended increasing efavirenz dosage from 600 mg to 800 mg a day when taken with rifampicin.103 Pharmacokinetic studies to assess whether nevirapine, a less costly alternative, can be used effectively and whether efavirenz can be given at 600 mg when combined with rifampicin, are underway. Other clinical issues needing further investigation include when to initiate HAART in patients with HIV tuberculosis co-infection and the challenge of multidrug resistant tuberculosis, which has increased significantly in the past decade.104, 105, 106, 107, 108, 109 The clinician should maintain a balance between the risk of morbidity and mortality from new opportunistic infections when starting HAART late and the risk of severe immune recovery inflammatory syndrome with or without additive drug related toxicity in initiating HAART during treatment for tuberculosis.110, 111 These complexities call for closer collaboration between tuberculosis and AIDS control programmes in managing patients co-infected with these diseases.
Another lesson from tuberculosis that bears exploration in Asian settings in the context of HAART is the application of the directly observed therapy (DOT) strategy. As with HAART, adherence to tuberculosis therapy is critical to treatment success, with poor adherence fostering the development of multidrug-resistant tuberculosis. The DOT strategy, the WHO standard of care for managing active tuberculosis,112 has been an effective means of enhancing adherence in tuberculosis treatment. In starting HAART, the critical phase is the first few months of therapy, when patients have the most symptoms and side-effects.113 Use of a DOT strategy during this phase could assist in early identification of complications and side-effects of antiretroviral therapy. Recent pilot studies have shown encouraging results: a pilot DOT programme for HIV-infected individuals with a history of poor adherence showed a significant reduction in plasma HIV RNA in those who remained in the programme.114 In South Africa, a programme building on the existing tuberculosis-treatment infrastructure to deliver ART to people with tuberculosis/HIV co-infection found high rates of treatment adherence.115 A strategy of use of an intensive phase of direct observation at the onset of HIV therapy, followed by the phasing in of self-administered treatment could be further explored in Asian settings.116
Many other HAART-related treatment issues arise in Asia. Non-B HIV-1 subtypes dominate in many countries.56 Fortunately, there is little evidence of subtype differences in responses or resistance to ARVs;117, 118, 119 however, from a treatment perspective, subtype-B based viral load and genotypic resistant assays need to be validated when used in non-B infected populations.120 But such techniques remain in the future for most of the region.
Most countries apply WHO guidelines for starting HAART in adults when the CD4+ cell count falls below 200 cell/μL or the patient becomes symptomatic.121 Yet, in most of Asia the capacity for measurement of CD4+ counts is insufficient. These guidelines call for substitution of the total lymphocyte count with a cutoff of 1200 cells/μL3 for starting HAART should CD4+ count be unavailable. However, although total lymphocyte count might be useful in identifying the need for prophylaxis of opportunistic infection in resource-constrained countries,121 a recent study of a pooled clinical trials cohort noted that it was not a sensitive technique for initiating and monitoring HAART.122 Thus, development of lower cost CD4 counting techniques is essential to support more effective HAART management in developing countries.123, 124, 125 However, in the absence of indications of the degree of immunosuppression (CD4+ cell counts and viral load), workers in both India and Thailand have shown that oral lesions such as oral candidosis, might be judged strong indicators of HIV-associated immunodeficiency.126, 127, 128
The preferred choice for HAART is an NNRTI-based regimen; however, in Asia the drug combinations available are often constrained by cost. For this reason, lower cost stavudine and lamivudine is often the main nucleoside backbone in the region, with low-cost nevirapine being the major NNRTI used in Thailand and India.49, 50, 129 In developed countries, nevirapine-related life threatening side-effects (hypersensitivity, Steven-Johnson's syndrome, and severe hepatitis) occurred in less than 1%.130 A review of Thai cohorts found severe hepatotoxicity arising at a substantially higher rate of 18·5 per 100 person-years (95% CI 11·6–27·8) in those on nevirapine-containing regimens.100, 131 A report of fatal lactic acidosis, associated with nucleoside reverse transcriptase inhibitor, from Taiwan showed that the estimated incidence of lactic acidosis was 4·4 per 1000 patient years in those on nucleoside analogues (95% CI 3·9–4·7 per 1000 patient years). All six cases were advanced HIV disease with median CD4+ count less than 50 cells/μL3 and stavudine was the most common cause of this life-threatening adverse event.113 Thus, as HAART access expands, newly recruited physicians in the region who prescribe antiretrovirals (nevirapine and stavudine, in particular) need specific training in antiretroviral-related toxicities, their detection, and their management. Physicians also need additional training in combined opportunistic infection and antiretroviral management, since most patients in Asia are clinically advanced at the time of their first visit.132, 133 Finally, long-term success of HAART will need physicians, family members, social workers, and community based organisations, including support groups for people living with HIV/AIDS, to work closely together to ensure that patients are prepared and supported both medically and psychosocially to recognise side-effects, seek appropriate care, and adhere closely to their regimens.
Many Asian countries have chronically underfunded healthcare systems, overpopulation, high illiteracy rates, weak social safety nets, unwillingness of people to use condoms, governmental prohibition of harm reduction approaches to HIV prevention, and widespread discrimination against those living with and affected by HIV. According to authorities and experts from around the region, these factors contribute to poor or inadequate response to HIV epidemics in their countries.55
The initial response in almost every country of Asia was denial, focusing on HIV/AIDS as an imported rather than indigenous disease. Many Asian countries found it extremely difficult to accept that sex work, injecting drug use, and same-sex behaviours existed in their countries, despite the fact that studies showed that from 5% to 20% of men were clients of sex workers.29 Sex education, condom promotion, and harm reduction for drug users all touched on political and religious sensitivities around the region. In the mid-1980s WHO through its Global Programme on AIDS (GPA) provided extensive financial and technical support for countries in the region to draft short and medium term plans to combat the epidemic. It was this initial global effort that encouraged the development of sentinel surveillance for HIV in southeast Asia.9
The systematic and prospective surveillance of HIV in at-risk populations, as done in most Asian countries now,134, 135 has been a key factor in raising political leaders' awareness and building commitment for HIV prevention and care. When HIV prevalence grows rapidly, as in Thailand and Cambodia, surveillance data alone made the case for urgent action. But when prevalence is still quite low and seems to be growing quite slowly, such data are less compelling and less likely to move decision makers to action. Unless such data are properly interpreted in a local country context with an Asian epidemiological perspective, and are used to advocate for adequate responses and to identify and direct appropriate programmes, it becomes a meaningless exercise in data collection. Unfortunately, despite the high rankings generally accorded Asian surveillance systems,134 significant gaps in coverage of key populations and quality problems remain, and few Asian countries have translated these data into effective prevention programmes, as can be seen by the continuing growth of epidemics throughout the region.
On the other hand, if surveillance data are comprehensive, regularly updated, properly interpreted, and relayed in an understandable form to policymakers, good and non-complacent leaders will take appropriate action, as they did in Cambodia and Thailand.136, 137 Active use of surveillance data in conjunction with other sources of information, models, and policy analyses can then help to convince both government and civil society of the consequences of action and inaction, and assist in directing the response to achieve the greatest effect.138, 139 In some other Asian countries response is now happening. Growing prevalence in Vietnam and closer examination of the national epidemic25, 140 is forcing reconsideration of the unsuccessful social evils approaches of the past. Surveillance data in China have moved leaders to take a more active role, leading to the formation of a high-level national committee for HIV prevention. But in many countries responses remain stalled, and national commitment to addressing the epidemic is weak. Better advocacy based on improved local understanding of the specific epidemiological and behavioural country situation and an understanding of the most urgent local prevention needs is needed to break this complacency.
Epidemiologically, almost all new HIV infections in Asia take place in those at increased risk (men who have sex with men, injecting drug users, clients, and sex workers), and their immediate longer-term sexual partners.43, 44, 45, 46 This occurrence means that adequately resourced efforts focused on achieving good coverage in these populations can literally turn epidemics around.
When early epidemiological studies in Thailand and Cambodia showed the key role of sex work and sexually transmitted diseases in HIV transmission, national leaders in both countries quickly stepped up prevention efforts. The Prime Ministers of both countries made HIV/AIDS a national priority. In Thailand, the national HIV/AIDS budget grew from US$0·68 million in 1988, 90% of which came from bilateral donors, to $82 million in 1997, 96% of which came from the Royal Thai Government (the budget was reduced to $35 million in 1998 during the Asian crisis but has been maintained at this level throughout 2002).141 This budget supported programmes in every government Ministry, by non-governmental organisations (NGOs) and communities, and in the private sector. In Cambodia, international resources were mobilised to fill the needs. Major nationwide prevention programmes were mounted not only for sex workers and brothel owners, but reaching out to the large client population, encouraging condom use in sexual encounters and improving care for sexually transmitted diseases (STDs).40, 136, 142 The public was widely informed of the risk and educated about HIV and its prevention through extensive and intensive programmes in the media, schools, workplaces, and other venues. In response, condom use rose to more than 90% and the percentage of men visiting sex workers was halved in both countries. figure 4 shows the benefits from this education in Cambodia—almost a million cumulative infections were averted and prevalence peaked at 3·3% then began to decline. Thailand had similar success, providing valuable lessons about the extreme effectiveness of properly focused and resourced prevention efforts in Asia.
The lessons learned in the successful responses in Cambodia, Thailand, and Uganda all point to the importance of leadership, commitment, and continued effort from all sectors of society, including people living with HIV and AIDS to a successful national response. These lessons have been learnt in other Asian countries. Recent attention by the Chinese leadership to the HIV epidemic, with the formation of a high-level national committee on HIV prevention is likely to galvanise similar responses there. Indonesia143 and Papua New Guinea have addressed HIV/AIDS as a developmental issue, calling for action and partnership with all civil sectors in the country.144 Such commitment and coordination will need to be expanded from national levels to provincial and sub-provincial levels. This expansion will be challenging for large countries like China, India, and Pakistan145 and needs careful planning in the many Asian countries that are now decentralising health services—eg, Indonesia and the Philippines.
But much more prevention coverage is needed in most of Asia, and urgently. Although most Asian countries have lower risk than Cambodia and Thailand, epidemics of 3–5% of adults are possible unless effective prevention efforts are in place. And rates of infection in the countries in transition are likely to accelerate in the near future. Yet, few countries have achieved substantial coverage of client and sex worker populations—in fact, many cannot even estimate the sizes of these populations.
STDs have re-emerged in China as a result of its open-door policy and economic and social reform.146 Urbanisation, increased spending power, and outside cultural influences are contributing to a rapid increase in STDs and expanding HIV spread. This increase in infection has led some to call for mandatory STD and HIV screening of sex workers, prostitution and pornography bans, and restrictions on the tourist industry.146 But in the long run, measures such as these will drive prostitution underground and make HIV/STD even more difficult to control. Instead, Asian countries need to learn from one another about what makes for successful HIV prevention.
Successful programmes are those that use NGOs to pilot prevention and care activities, but then collaborate with governmental entities to move them to scale. An example is the collaboration between the International Voluntary Services organisation and the Women's Union of Ho Chi Minh City to provide STD care, education, and services to sex workers or the TRANSSEX project educating transport workers and sex workers to become peer educators for HIV/AIDS and STD prevention.147, 148 NGOs often have a catalytic role, leading in the development of new services and then fostering their adoption by the government. A good example is the anonymous clinic of the Thai Red Cross Society, which within a year of its opening, successfully lobbied the Thai government to lift the ministerial act requiring all laboratories to report the names and addresses of those with HIV to the Ministry of Public Health, and led to the government implementing voluntary counselling and testing services in every province.149 But many more such programmes are needed in Asia. HIV services for clients and sex workers remain restricted in most places.
Furthermore, no Asian country has good prevention programmes for men who have sex with men, and there has been strong resistance to adopting proven needle exchange and harm reduction approaches for injecting drug users as national policy.150 As such, older epidemics in injecting drug users and men who have sex with men continue unabated, potentially fuelling epidemics in sex workers,36 and new epidemics are arising constantly. As a consequence of this failure to address prevention effectively, HIV continues its march through Asia.151 Recent epidemic growth in China, India, Indonesia, Nepal, Vietnam and other countries give testimony to this statement.
Care is generally regarded as the expensive arm of the entire HIV/AIDS prevention and control programme. For countries such as Bangladesh with limited resources and few reported HIV infections, care was completely left out of the National AIDS/STD Program of Bangladesh until 2003.152 However, once the epidemic is established, the need for treatment and care is unavoidable, and antiretrovirals are now a mainstay of HIV care. Health care infrastructures vary widely across the region, but are weak in many places, limiting many people with HIV/AIDS to palliative care, often at home. Access to HIV testing is limited, and most of these people first learn their HIV status after developing serious symptoms that need medical care. Additionally, strong stigma and discrimination in much of the region keep many from accessing the care they need.153, 154 The move towards wider antiretroviral access will help, but many barriers first need to be overcome.
One of the few developing countries in the region with much experience with antiretrovirals is Thailand. Thailand has built the medical infrastructure needed to manage and research antiretroviral care for those with HIV and AIDS, which serves as a positive example for other countries. Antiretrovirals have been provided free to poor HIV-positive Thais since 1992, although access was scaled back in 1995 because of growing budgetary demands related to the high costs of antiretrovirals.155 Since that time, Thailand has begun generic production of several antiretrovirals, drastically reducing the cost. A fixed dose combination of stavudine, lamivudine, and nevirapine costs only US$1 per day. With these price reductions and increased funding from both the government and the Global Fund for AIDS, Tuberculosis and Malaria, the Royal Thai Government plans to expand antiretroviral support from 13 000 to 50 000 patients in 2004, using this combination of drugs as the first-line HAART regimen.
Important lessons have been learned in Thailand about providing national level access to antiretroviral programmes for people living with HIV/AIDS. Several prerequisites and actions are needed in parallel to ensure efficient access to HAART: (1) committed leadership at the policy level; (2) significant reductions in ARV costs; (3) strengthening of the health care system and infrastructure; (4) expanded ability of care providers to manage HIV care through training to improve attitudes and build knowledge and skill in treatment of patients with HAART; (5) reduced cost for treatment monitoring, especially CD4+ counts and viral loads—eg, a generic monoclonal anti-CD4 reagent costing US$2 per test has been developed in Thailand;123 (6) comprehensive patient education on the principles of HAART, adherence, and its toxicity; (7) involvement of the community (non-profit organisations and people living with HIV/AIDS groups) in the process; (8) locally relevant clinical research—eg, HIV-NAT at the TRC-ARC has been doing many clinical trials, which not only contribute to region-specific HIV care, but provide HAART access for over 1500 patients;51, 52, 117 and (9) gaining supplemental international funding support—eg, from the Global Fund for AIDS, Tuberculosis and Malaria.
Nonetheless, several challenges remain for Thailand and other Asian countries in providing access for all, including weaknesses in management systems, limited resources, drug resistance,119 and the higher costs of second-line and subsequent therapies.156 Another challenge will be expanding access to voluntary counselling and testing to link those who test positive with early HIV care. Established in 1991, the anonymous clinic of the TRC-ARC157 has expanded services to include counselling and testing for CD4 counts and viral loads, and chemoprophylaxis for pneumonia P carinii, and cryptococcal meningitis for the immunocompromised.
Thailand has also been a leader in the prevention of mother-to-child transmission of HIV, successfully implementing nationwide coverage.158, 159 After the ACTG076 protocol established that zidovudine could reduce mother-to-child transmission,160 the TRC-ARC and partners launched a public donation campaign in 1996 to provide a modified form of treatment set out in the ACTG076 protocol to poor HIV-positive pregnant women throughout Thailand. Vertical transmission fell to 5·8%, showing the effectiveness of the protocol in a non-clinical-trial setting.161 With supplemental support from Columbia University this programme is now being extended to provide lifelong antiretrovirals to mothers and other infected family members after delivery.162 Once the Bangkok short-course zidovudine study, which was controversial at the time,163 showed the effectiveness of short-course treatment,164 operational trials began immediately to implement this as national policy.158 In the first quarter of 2004, single-dose nevirapine was added for both mothers and newborn babies in hopes of further reducing transmission.165 However, recent findings of neviripine resistance in 24% of women receiving the drug near the time of delivery and 46% of their infants,166, 167 raise concerns about the choice of antiretrovirals for prevention of mother-to-child transmission which could compromise later therapeutic options.168 Further study is needed to find suitable combinations of antiretrovirals for these women to avoid development of resistance.
The first Asian HIV vaccine trial started in June, 1994, in Thailand169 and has been followed by many more, including two efficacy trials (table 2). The recently terminated Vaxgen trial recorded that the vaccine was non-efficacious.170 In mid-2004, TRC-ARC and Australian collaborators will launch a phase I/II trial of an HIV DNA vaccine boosted with fowlpox recombinant vaccine in Thai volunteers. This trial represents a new model of HIV vaccine development outside the pharmaceutical arena with a clear-cut partnership role of the host country or host institution.171 Several novel vaccine trials are planned in China and India: recombinant modified vaccinia Ankara in India, HIV DNA primed and recombinant MVA boost trial in China, and recombinant Semliki Forest virus subtype A, C in India. The transfer of manufacturing technology from a biotech company to an Indian firm for vaccine production for a larger phase trial has been planned, providing opportunities for expanded production in the future.
International collaboration has played an essential part in prevention, basic research, clinical trials, operational research, and capacity building in the region. American, French, Australian, and Japanese universities and government agencies have been major collaborating partners throughout Asia, especially in Cambodia, China, India, and Thailand. Examples of bilateral research collaboration include the joint US-Thai CDC collaboration study short-course zidovudine for prevention of mother-to-child transmission of HIV and joint US-Thai Armed Forces research on HIV vaccines.164, 172 The HIV-Netherlands, Australia and Thailand Research Collaboration (HIV-NAT) is a good example of a three-continent collaboration in HIV clinical trials and patient care, enrolling more than 1600 patients in various antiretroviral trial protocols until the end of December, 2003.173
The role of the Global Fund is expanding, and a growing number of Asian countries have received funds from the Global Fund for AIDS, Tuberculosis and Malaria.174 China, India, and Thailand have benefited the most from the these funds. However, several constraints restrict the Fund's effect: (1) grant proposal writing and fund release are still complex and need to be simplified; (2) care should be taken that such funds not replace national resources, but instead stimulate expanded national resource allocations in the upcoming years to ensure adequate prevention and care coverage is achieved; (3) local NGOs or institutions should be able to apply directly to GFATM without going through the country coordinating mechanism when conflicts of interest occur or government refuses to address key issues. Most country coordinating mechanisms still do not have effective, transparent, and accountable working mechanisms; (4) the GFATM should not exclude operational research, because it is essential to strengthen the infrastructure and generate the systematic knowledge needed for efficient and effective implementation of prevention and care.
Although a few countries in Asia have lost their chance to prevent the wider spread of HIV infection, others can still do so. Lessons from Thailand and Cambodia have shown that targeted interventions work, but only if implemented with high coverage and sufficient intensity. Few Asian countries have achieved these aims, and prevention will become even more essential as antiretroviral access potentially increases risk behaviour. Once HIV infection has become established, growing needs for care and treatment are unavoidable. Expanding access to antiretrovirals offers people with HIV/AIDS in Asia hope, but it must be complemented by country-specific research, which acknowledges the cost, accessibility of antiretrovirals, and medical management constraints faced in each location. And unless prevention programmes are strengthened simultaneously, the increasing flow of new infections will eventually make expanded access unsustainable in much of Asia. Now, more than ever before, treatment and prevention programmes clearly need to be integrated in ways that complement and boost each other's effectiveness and efficiency.
