WHO Draft Guidelines for Antiretroviral Therapy in Resource Limited Settings
.By Lisa A. Spacek, M.D., Ph.D.

• When to Initiate HAART
• Which HAART Regimen to Start
• When to Change Theapy
  • Table 1: WHO Recommendations for Initiating Antiretroviral Therapy in Adults & Adolescents With Documented HIV Infection
• What to Change To
• How to Monitor
  • Table 2: WHO Guidelines for Laboratory Monitoring of Antiretroviral Use
• Conclusions

On April 22, 2002, the World Health Organization (WHO) approved draft treatment guidelines for HIV-infected people in resource limited settings and recommended that 12 antiretroviral drugs be added to the Essential Medicines List. The primary purpose of the guidelines is to serve as a framework for health care policy leaders in developing nations as they begin to implement HIV treatment programs. The intent is to expand access to highly active antiretroviral therapy (HAART) to at least three million people with HIV/AIDS in Africa by 2005. This is a decisive step in advancing HIV care as a complement to established efforts in HIV prevention. However, the task of expanding access to HAART by more than a ten-fold increase is daunting, especially in settings where basic healthcare infrastructure is lacking.

The WHO guidelines were published in the wake of the launch of The Global Fund to Fight AIDS, Tuberculosis and Malaria, a public-private partnership led by United Nations Secretary General Kofi Annan. The Global Fund to awarded $378 million USD to 40 programs in 31 countries. An additional $238 million USD will be awarded in the second round of funding, for a total of $616 million USD. Of the $378 million USD awarded in the first round, approximately 60% or $227 million USD will fund HIV/AIDS projects, and an additional 15% or $57 million USD will fund projects that address HIV/AIDS plus one or both of the other diseases (TB and/or malaria). The combined efforts of inter-national entities such as WHO, UNAIDS, and the Global Fund along with local public health officials and health care providers will be necessary to face the formidable challenge of providing HIV treatment to the millions of people with HIV/AIDS.

The numbers of people infected with HIV in developing nations continues to increase daily. WHO estimates that 36 million adults and children in the developing world are living with HIV infection. Death rates due to HIV-related illness in developing nations are equally catastrophic. In sub-Saharan Africa in 2001, 2.3 million people died from AIDS [UNAIDS, Dec. 2001]. This is in stark contrast to the peak death toll of 51,117 recorded in 1995 in the United States, which decreased to 15,245 in 2000 [CDC, HIV/AIDS Surveillance Report 2002;13]. The reasons for this disparity are multifactorial, but include limited access to care, including antiretroviral therapy and treatment for opportunistic infections, lack of technical and human resources, and insufficient funding to support either prevention or treatment. The objectives of the WHO draft guidelines address the following topics:

1. When to initiate HAART
   
2. Which HAART regimens to start
   
3. When to change therapy
   
4. Which alternative regimens to change to
   
5. How to monitor patients in resource limited settings
   

Additional topics include treatment of patients with concomitant medical conditions such as pregnancy, tuberculosis, and hepatitis. The draft guidelines are meant to standardize and simplify antiretroviral treatment without compromising the quality and outcomes of therapy.

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When to Initiate HAART

In resource-limited settings, the WHO recommends initiation of therapy based on clinical staging and CD4 lymphocyte count or total lymphocyte count. WHO Stage I includes those HIV-infected individuals who are asymptomatic or manifest persistent generalized lymphadenopathy; Stage II includes those with weight loss (<10% of body weight), minor mucocutaneous manifestations, herpes zoster, and recurrent upper respiratory tract infections; Stage III includes those with weight loss (>10% body weight), unexplained chronic diarrhea, unexplained prolonged fever, thrush, oral hairy leukoplakia, pulmonary tuberculosis, severe bacterial infections, and those bed-ridden for less than 50% of the day during the past month; and Stage IV includes those with clinical syndromes consistent with AIDS and/or who have been bedridden for greater than 50% of the day during the past month. The guidelines, shown in Table 1, below, recommend starting HAART in all patients with WHO Stage IV disease irrespective of CD4 lymphocyte count and in those with WHO Stage I, II, or III disease who have CD4 lymphocyte counts below 200 cells/mm³ in areas where CD4 lymphocyte count is available. If CD4 lymphocyte count is unavailable, HAART is recommended in those with WHO Stage II or III disease with total lymphocyte counts below the range of 1,000 to 1,200 cells/mm³. Assessment of HIV viral load is not considered essential for determining the need for therapy.

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Which HAART Regimens to Start

Recommendations for first-line HAART regimens include AZT/3TC accompanied by abacavir, efavirenz, nevirapine, nelfinavir or ritonavir-boosted indinavir, lopinavir or saquinavir. The combination of AZT/3TC/ABC is considered the most “user-friendly” regimen, as pill burden is minimal. This combination can be used during tuberculosis treatment without concern for drug interactions. The disadvantages include potency, cost, and the potential for serious or even fatal hypersensitivity reactions that could escape detection in resource-poor settings. In regions with a significant prevalence of infection with HIV-2 and HIV-1 Group O virus the recommendation is to avoid the use of NNRTI-containing regimens except in patients with documented HIV-1 infection, given the inherent resistance of HIV-2 and Group O HIV-1 to these drugs.

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When to Change Therapy

Determination of the need to change therapy is based primarily on treatment failure and toxicity. Without routine assessment of HIV viral load, providers in resource limited settings will have to rely on clinical failure of therapy defined as “clinical disease progression with development of an opportunistic infection or malignancy when the drugs have been given a sufficient time to induce a protective degree of immune restoration.” Likewise, with limited laboratory monitoring to detect early signs of renal, hepatic or hematologic dysfunction, toxicity will manifest as clinical syndromes of renal failure, hepatitis, or anemia. Most concerning is the potential for morbidity and mortality related to advanced stages of drug toxicity that could have been detected earlier if greater resources were available.

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What to Change To

The recommendations for second-line regimens to be used in the event of treatment failure reflect the recognition that without viral load and drug resistance monitoring, virologic failure will have been present for an extended period prior to clinical treatment failure. Therefore, the development of drug resistance patterns based on early viral genetic mutations may differ from virologic resistance developed over prolonged antiretroviral exposure. In general, second-line regimens intended to follow AZT/3TC-containing regimens include d4T/ddI in addition to either NNRTIs, ritonavir-boosted PIs, or a combination. Further support for the initial use of AZT/3TC/ABC is due to the ability to spare both NNRTIs and PIs. This allows for a more potent salvage regimen in light of the high likelihood of extensive nucleoside resistance developing prior to clinically apparent treatment failure. If available, tenofovir could be used in salvage regimens because of its antiretroviral activity in some patients with nucleoside resistance.

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How to Monitor

In addition to the assessment of immunologic function as indicated by symptoms, clinical signs and lymphocyte count, laboratory testing for the safe and effective use of HAART is divided into four categories: absolute minimum tests, basic tests, desirable tests, and optional tests (Table 2, below). Absolute minimum testing includes an HIV antibody test and hemoglobin or hematocrit level. Basic testing adds white blood cell count and differential, liver enzymes, serum creatinine and/or blood urea nitrogen, serum glucose, and pregnancy tests for women. Desirable tests include bilirubin, amylase, lipid levels and CD4 lymphocyte count. Testing for HIV viral load was deemed optional.

Given that HIV viral load testing is unlikely to be available in resource-limited settings, routine evaluation of HIV resistance is also unlikely to be available. Because it is necessary to monitor HIV resistance and document trends in antiretroviral drug susceptibility, the WHO, in collaboration with the International AIDS Society, is instituting a Global HIV Drug Resistance Surveillance Network. The goals of this effort will be to establish institutional networks by which to monitor drug resistance and disseminate region-specific strategies to address drug resistance patterns.

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Conclusions

The WHO guidelines are based on rigorous evaluation of data collected almost exclusively in developed countries. Of concern is whether guidelines created for HIV-infected populations of developed nations are adaptable to HIV-infected populations worldwide. Specifics regarding the presence of different HIV subtypes, endemic infections such as tuberculosis, genetic determinants, and other health measures such as nutritional status may introduce factors that alter response to treatment.

Developing nations that have successfully implemented HAART include Brazil, Thailand, Senegal, and Uganda. Studies are needed to examine responses to HAART and whether changes to the guidelines would better serve populations in different regions around the world. For example, initiation of HAART earlier in the course of HIV disease may have an impact on disease outcomes due to endemic mycobacterial infections such as tuberculosis. With initiation of HAART on a population-wide scale, continuous surveillance of drug-resistant HIV will be needed to update treatment guidelines. A recent study conducted in Gabon demonstrated resistance to antiretroviral therapy [J Acquir Immune Defic Syndr 2002;29:165-168]. Of great concern is that antiviral drug resistance due to suboptimal therapies could limit the potency of available treatments.

Multiple studies conducted in developed nations have proven the tremendous benefit of HAART with its resulting dramatic decline in both morbidity and mortality. In developed or developing nations, HAART provides the only hope of survival for those with HIV infection who are able to adhere to daily lifelong therapy. Moreover, the availability of HAART can further enhance prevention activities by offering incentives to seek HIV testing, preventing mother-to-child transmission, and decreasing the risk of sexual transmission. The development of these WHO draft guidelines is a significant and definitive step toward expanding access to life-saving therapy to people living with HIV/AIDS worldwide. The WHO draft guidelines of April 22, 2002 are available online at: http://www.who.int/HIV_AIDS/HIV_AIDS_Care/ARV_Draft_April_2002.pdf.