American Foundation for AIDS Research, August 2002
Anne-christine d'Adesky

Introduction

The 14th International AIDS Conference that took place last July in Barcelona, Spain reflected significant pro-gress in providing global access to HIV treatment. Four years ago, global access was dismissed at the 12th Conference as an impossible dream, and it remained highly controversial two years ago at the 13th Conference in Durban, South Africa. Only about 1% of the world's estimated 40 million people with HIV are getting lifesaving antiretroviral medicines, but national treatment projects are now being planned or implemented in the hardest-hit countries of sub-Saharan Africa and Asia. These are often grafted onto existing community-based HIV prevention programs, including those to prevent mother-to-child transmission (PMTCT), as well as maternal health programs. Others represent expanded TB-, STD- or malaria-control programs since many patients are coinfected with these endemic diseases.

Pushing the Treatment Envelope

The World Health Organization recently announced a goal of treating 3 million people with HIV by the year 2005. Throughout the world, though, poverty and lack of funding are still major barriers to treatment access. The new UN-backed Global Fund for AIDS, TB and Malaria so far has attracted only about a quarter of the desired $10 billion per year in funding commitment. ACT UP groups furiously disrupted a conference speech by U.S. Health Secretary Tommy Thompson to demand additional funding for treatment under the Global Fund.

Rather than adding more money directly to the Global Fund, as Congress was considering, the Bush administration recently announced a separate three-year package of $500 million to launch PMTCT programs in poor countries. Eight African countries and those in the Caribbean will initially benefit from the program, which aims to reduce target countries' MTCT by 40%. The program will offer voluntary counseling and HIV testing along with prophylactic nevirapine. Anti-HIV treatment will be offered instead of short-course nevirapine to some mothers and infants in poor countries with stronger health systems. Bush officials said this initiative would serve as an entry point for introducing AIDS care and help build up infrastructure.

Thompson defended the U.S. position, arguing that the Bush administration has committed more money to the Fund than any other nation. In a media briefing after his disrupted speech, he said the U.S. plan is "directly in response to requests by African health ministers who told us this is exactly what they want." African policy makers, he said, backed a scaled up approach that will use prevention programs as the infrastructure for phase-in treatment programs.

Activists reject that logic as short-sighted, unethical, and too late, arguing that is may save infants now, but abandons their parents and millions more to a certain death sentence from AIDS. Moreover, they noted that poverty-stricken Rwanda gives 8% of its Gross Domestic Product to the Global Fund, far more proportionately than U.S. which contributes 0.005% of its GDP.

American donors such as the Gates Foundation and the United States Agency for International Development have also pledged millions to back new global HIV initiatives, but the scale is small given the need. As Malaysian human rights advocate Irene Fernandez re-minded conference participants in a fiery plenary speech: "Communities have the capacity and knowledge to address AIDS. It is not the knowledge that is the bottleneck. It is lack of resources."

Despite the financial shortfall, various local agencies have pushed ahead, only to confirm what activists long contended: treatment means hope, which provides an effective weapon to help combat widespread panic over HIV/AIDS. Stigma and discrimination against people with HIV remain a major obstacle to receiving care or support from their families and communities. The prospect of therapy is bringing AIDS and persons with HIV out into the open. It has spurred more people to get HIV testing and counseling — the first steps to getting care. It also is helping generate new discussions of sexuality and of the underlying social and cultural issues that affect access to health care for women and even more vulnerable groups — sex workers, homosexuals and IV drug users.

In Malawi, for example, the ProTest pilot project in Lilongwe District was set up in January 2000. Its purpose is to increase voluntary counseling and same-day HIV testing as part of a package of HIV/TB interventions. The program trained community-home care volunteers and traditional healers, and referral links to care services were set up. The result has been a four-fold increase in clients tested at the counseling centers. Individuals willingly sought HIV and TB services, and 95% were screened for TB and HIV. As of November 2001, 60 people were receiving preventive TB therapy, and 300 people were undergoing treatment for HIV, while condom distribution had increased.

Similar results were reported from other voluntary counseling and testing (VCT) sites under study as entry points for anti-HIV therapy. Taken together, they suggest that as treatment programs expand, more people are likely to become aware of their HIV status and seek care, putting further pressure on public health systems to deliver services. The investment in HIV programs is seen by many as a promising starting point for strengthening public health systems overall.

Projects in Thailand and South Africa illustrate how community involvement and education of local stakeholders are key to assuring long-term "ownership" and success of new treatment programs (Conference abstracts TuPeG5665, TuOrG1246 and ThPeB7264). Some advocate a greater decentralization of new resources away from big cities and into rural sectors, a strategy aimed at increasing access by providing services directly where patients live. This approach calls for a greater investment in existing home-based HIV programs and training of lay health providers, midwives and traditional healers along with physicians and nurses in district hospitals.

Some groups in the U.S. and elsewhere are pushing an adherence strategy of Directly Observed Therapy, or DOT (abstracts WePeB5868, B10598, TuPeE5208 and ThPeB7276). This approach, which comes from TB control, is showing mixed success. In some settings, positive individuals and traditional healers are being successfully trained to help patients adhere while other projects note the important role of community and family support (Conference abstracts WePeF6667 and ThPeB7264).

Poverty increases the difficulty in adhering to treatment dosing schedules. In Zambia, Helen Ayles of the Zambart Project described how hunger plays an important role in non-adherence (abstract MoOrC1103). Simply put, it is hard to take pills without food. They induce nausea and vomiting. This is a serious issue even in successful HIV DOT project like rural Haiti. Food and nutrition are an integral aspect of HIV treatment that have been largely overlooked and underfinanced.

Coinfections Vary around the World

Small teams of physicians and nurses in community clinics and district hospitals around the world have proven that they can administer HIV therapy once there has been a modest investment in physician training, patient education, diagnostic testing equipment and drugs. But the task is harder in poor settings. Patients are often diagnosed late in HIV disease and typically suffer from chronic malnutrition and coinfections such as dysentery, TB, hepatitis B and C, malaria and STDs. Many clinics rely on symptom-based HIV disease management, which focuses on visible physical signs of disease, because viral loads and sometimes even blood cell counts are unavailable.

The effect that TB and HIV have on making each other worse is well documented. New studies warn that HIV patients in sub-Saharan Africa may have an increased risk of severe malaria (abstracts ThPeC7602, ThPeC7604 and ThPeC7607). HIV drugs such as AZT and malaria both contribute to anemia, a common condition seen in African and Asian patients on therapy. There are other coinfections to watch for, including HIV-2, a sister virus to HIV-1 that is prevalent in West Africa, and HHV-8, a herpes virus linked to Kaposi's sarcoma that has turned up to a high degree in East African sentinel surveys (abstract TuPeA4427).

A Conference report from South Africa found that the most common opportunistic infections among HIV patients visiting poor township clinics were, in descending order: oral thrush, pulmonary and extrapulmonary TB, recurrent vaginal thrush, oral hairy leukoplakia, and recurrent herpes (abstract MoPeB3238). This study confirmed that even nurse-based clinics could manage HIV patients if essential drugs like acyclovir and fluconazole are available to treat OIs.

A few examples of success: The government-funded Senegalese Initiative on Access to Antiretrovirals that began four years ago in Dakar (abstract MoPeB3225). It produced quick results. A triple combination regimen was given to 470 treatment-naïve individuals with symptomatic HIV (baseline CD4 count of 150 cells/mm³ and baseline plasma viral load of 81,650 RNA copies/mL). Therapy reduced 85% of patients' HIV viral loads to below 200 copies after one month. Their CD4 counts doubled after 18 months and climbed to 280 after the three-year cutoff point of the study. The most common side effects were anemia and polyneuritis. After 39 months of follow-up, 86% of patients had taken at least 80% of their drugs, and only five had dropped treatment. There were 20 deaths during the follow-up period. The Dakar program made use of a new, relatively cheap diagnostic technology called Dynabeads to measure CD4 counts. Other projects hope to import the low-cost CD4 count tests and other diagnostic kits now in development (see the amfAR Treatment Insider, February 2002).

In Johannesburg, South Africa, a pilot project is underway with the backing of the International Solidarity Fund (abstract WePeF6677). It plans to treat 100 people. As of July, 53 adults and 19 children with ad-vanced HIV disease (average CD4 count of 97 copies/mm³ and viral load count of 280,000 RNA copies/mL) were started on triple drug regimens. After 12 weeks on therapy, the first ten patients had viral load levels below 400 RNA copies/mL and were improving, though their weight had not increased significantly. Three individuals dropped out of the study; one patient died from severe pneumocystis pneumonia, and one developed serious neuropathy. So far, the project has had a favorable impact on the clinical course of disease in this group. Patient and family participation contributed to a 98% rate of adherence to therapy.

Exploring the Downside

Problems of drug side effects, resistance and adherence have all cropped up in poor societies as in rich, but the long-term picture may prove more problematic for developing countries. For example, drugs of any class can cause liver damage and exacerbate latent hepatitis (abstracts TuPeB4534 and LbOr15). Attention to liver toxicity is a prime necessity but may be particularly problematic in resource-poor settings. Furthermore, an Emory University study in an American inner city clinic observed that drug-related side effects such as lipodystrophy and neuropathy occurred more often in women than in men (abstract WePeB5968). This observation may portend greater side effect issues in developing countries, where more women than men have HIV.

So far, typical mild side effects seen with non-protease inhibitor regimens have been anemia, nausea, headache, rash, and neuropathy. But more serious side effects such as pancreatitis and liver toxicity have also turned up. A Doctors without Borders pilot HIV therapy program in Khayelitsha, a poor township near Cape Town, found that 45% of women reported some therapy-related adverse event such as nausea, rash, and head-aches (abstract WeOrB1303). The researchers found such laboratory abnormalities as neutropenia and elevated liver enzymes in the blood. The incidence of these side effects was judged "similar to those seen in other groups and should not be a justification to withhold HAART."

The news about drug resistance is mixed. A sentinel resistance survey from Gabarone, Botswana reported very low prevalence of the major (primary) drug resistance to all classes of HIV drugs among a group of treatment-naïve individuals (abstract TuPeB4607). But it also found significant rates of secondary resistance mutations to protease inhibitors appearing during treatment, though "the clinical significance of this remains to be elucidated." Botswana's government will push forward with its plan to use NNRTIs and nucleoside analogs. In the Senegalese Access cohort mentioned above, 13 patients of 131 had HIV with emerging resistant mutations during follow-up. Other studies found that resistant mutations arise over time but patients may still be healthy. That makes it important to distinguish between mutation patterns and clinical outcome (see the amfAR Treatment Insider, August 2001).

Learning from MTCT

New insights have come from a large number of mother-to-child transmission programs launched over the past few years. The general view confirms that use of short-course HIV drugs like AZT, 3TC and nevirapine in MTCT protocols are safe and effective in reducing transmission to newborns. Some groups are looking at how short to go, and whether postnatal MTCT prophylaxis given to HIV-positive nursing mothers or to newborns can be effective. A study in 223 Zimbabwean pregnant women compared the use of an "ultrashort" AZT regimen (the drug given at the onset of labor, during labor and every six hours to the newborn for 72 hours after delivery) to the well-documented "Thai protocol" (abstract MoPeD3680). The Thai protocol uses a four-week course of AZT given at the end of pregnancy and has been found to reduce perinatal transmission by 51% in clinical trials.

Here, the ultrashort protocol study group had an in-creasing advantage over the Thai protocol group to six months. Postnatal transmission due to breast-feeding, which was adopted by almost all the women in both arms of the study, was similar in both study arms. After six months, 30% of the babies on the Thai protocol arm of the study were infected compared to 24% in the ultrashort protocol arm. (This trend did not reach statistical significance.)

This and other reports highlight a high risk of postnatal infant exposure to HIV through breast-feeding, which often blunts the initial benefit of MTCT initiatives. A National Institutes of Health meta-analysis of nine MTCT clinical trials called the Breast-feeding and HIV International Transmission Study reviewed the patient charts of 1,509 children (abstract TuOrB1177). It found an overall postnatal transmission rate of 25% (378 HIV-positive children).

Although it is thought to be safer for women either to exclusively breast-feed or to use infant formula than adopt a mixed feeding strategy, new reports show many women cannot sustain either choice. For some, stigma and fear of HIV disclosure affect their decision and the reaction of partners, family and community limits or boosts their adherence (abstract TuOrB1178). For others, economics play a role when there is no money to buy formula (abstracts TuPeF5419, WePeB5931, MoPeD3683 and F11979).

At the Nsambya Hospital in Kampala, Uganda, a government-run PMTCT program was started in January 2000. Out of 684 HIV positive women, 374 en-rolled in the program and were given either short-course AZT or nevirapine. At delivery, 54% decided to exclusively breast-feed, and the others chose to use only infant formula. Within the first three months, many women in both groups admitted to mixed infant feeding. After six months, the rate of HIV transmission in the original breast-feeding group was 18%. In the formula-feeding group, the rate was only 4%. The transmission rates were similar whether AZT or nevirapine was used to control MTCT. Death, illness and weight gain also were comparable regardless of the feeding method.

Unfortunately, large numbers of pregnant women arrive in delivery rooms without prior prenatal care. It is difficult to provide them with HIV testing and adequate counseling at this time. Some advocate using the new rapid HIV tests for such cases (abstracts TuPeC4766 and D11326). Women belatedly found to have HIV and their newborns could be offered immediate therapy, including cesarean sections. But the consequences of inadequate counseling and ill-conceived HIV status disclosure can be dangerous. The negative psychological impact of testing new mothers includes heightened risk of depression and suicide. Also, a South African study found that disclosure to partners often triggers domestic abuse and violence (WePeF6690).

The United States has obtained an MTCT under 2% by administering triple-drug combination therapy to pregnant women, performing cesarean sections at delivery, and exclusive formula feeding of infants. Several reports at Barcelona noted similar results, including a large multicenter study from Spain that began in early 2000 (abstract C10694). MTCT rates in this study were 0.8% and 9% for treated and untreated mothers, respectively. Other studies found that most women, including pregnant women, tolerate anti-HIV drugs well (abstracts TuPeB4455 and MoPeD3682).

Coming Soon: MTCT-Plus

One of the high notes of the conference was the an-nouncement of the first MTCT Plus initiative, which was backed by the World Health Organization and several foundations. This 12-site program is promoting a family-centered approach to HIV therapy. It plans to offer HIV therapy to symptomatic pregnant women, their infected partners and children. Many of the details are still on the drawing board.

Dr. James McIntyre's Soweto clinic is one of the sites: "We see this as an opportunity to see how it is to understand the issues around treating big cohorts," he explained. "We can begin to get a handle on what would really be needed to provide them with comprehensive care."

The MTCT Plus program in Soweto will begin by offering drugs to positive mothers post-delivery and watch how they affect postnatal transmission rates. Al-though McIntyre is optimistic, he worries that insufficient effort is being taken to educate and involve HIV-positive women and other community members in the program's implementation.

"Even with mothers, it worries me to have a rapid rollout without adequate training," he explained. "I think we're finding that you have to emphasize the important side effects, for example. Everybody says, ‘Well, the side effects of these drugs will be nausea,' but they don't say, "If you have abdominal pain, get in here." McIntyre is most concerned about liver toxicity and notes that no one has yet advocated routine hepatitis screening for pregnant women.

TB is another concern, as is malaria. "People have to start thinking, 'What are the building blocks that we can start building up everywhere to start layering [HIV therapy] on?" summed up McIntyre. "There's kind of a rush to treat everywhere, correctly for some reasons, but incorrectly for others, because we haven't thought of what is needed. I think we have to make sure that we have TB-friendly and pregnancy-friendly regimens."

In two years, the world will meet again in Bangkok to measure how much progress has been made. "Everything is moving very quickly, and there is so much to do, it's mind-boggling," summed up McIntyre. "But at least things are moving in the right direction now on the treatment front. You have to be optimistic about that."

This article has been reprinted from the Treatment Directory at amfAR.org

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