1. Cotrimoxazole prophylaxis
In industrialized countries, the combination antibiotic trimethoprim-sulfamethoxazole (or cotrimoxazole) has been recommended to prevent Pneumocystis jiroveci (formerly P. carinii) pneumonia (PCP) in HIV-infected adults with CD4 counts of less than 200 cells/�l since 19891 and in children born to HIV-infected mothers since 1991.2 Cotrimoxazole prophylaxis is standard practice in areas of the world where PCP is common in HIV-infected persons. PCP appears to be less common in sub-Saharan Africa than in other regions,3 but cotrimoxazole is also effective in African countries in preventing diarrhea and malaria and in prolonging life.
Several studies have addressed the efficacy of cotrimoxazole in HIV-infected persons in sub-Saharan Africa. A randomized placebo-controlled trial of cotrimoxazole prophylaxis for HIV-infected adults (WHO clinical stage 2 or 3) in Cote d�Ivoire demonstrated a reduction of the rate of severe events (death or hospitalization) by 43 percent in the intervention group, but did not show a decline in mortality.4 Another randomized trial in Cote d�Ivoire of cotrimoxazole prophylaxis for HIV-infected adults with active pulmonary TB showed a 46 percent reduction in mortality and a 43 percent reduction in hospitalization.5 A study in South Africa found that cotrimoxazole reduced mortality by 44 percent and severe HIV-related illnesses by 48 percent in patients with WHO stage 3 or 4 disease or with CD4 counts less than 200 cells/�l.6 These findings were further supported by a meta-analysis of randomized trials in adult African HIV-infected patients, which showed that cotrimoxazole reduced death by 31 percent, morbidity by 24 percent and hospitalization by 34 percent.7 In a recent study in Uganda, cotrimoxazole, when taken daily by persons with HIV, reduced death by 46 percent, malaria by 72 percent, diarrhea by 35 percent, and hospitalizations by 31 percent. It also slowed the rate of CD4 decline and the rate of viral load increase.8 PCP appears to be more common in HIV infected African children than in adults, and one study that evaluated the efficacy of cotrimoxazole prophylaxis in South African children documented an 89 percent reduction in PCP incidence.9
Several criteria for cotrimoxazole prophylaxis eligibility in African patients have been proposed: Wiktor et al. found the benefit of cotrimoxazole was most significant in patients with CD4 counts less than 350 cells/�l,5 and Badri et al. suggested prophylaxis for patients at WHO clinical stage 3 or 4.6 However, Anglaret et al. found benefit at all CD4 levels,4 as did Mermin et al.8 A cost-effectiveness study by Yazdanpanah also recommended prophylaxis for adults with WHO stage 2, 3 or 4;10 another by Pitter et al. reports cost-savings when cotrimoxazole is given to all HIV-infected adults in Uganda (Dr. Christian Pitter, personal communication). National recommendations in Uganda suggest cotrimoxazole for all HIV-infected persons.
Cotrimoxazole is relatively safe and available, does not require laboratory monitoring, and in the Ugandan study, its effect did not decrease over the 1.5-2 year follow-up period.8 The most common toxicity - skin rash - appears to be uncommon in African patients, and its severe manifestation - Stevens-Johnson syndrome - is rare.4,5 Cotrimoxazole is widely available in sub-Saharan Africa and when purchased in bulk costs only $6 per person per year. Concerns remain about the generation of widespread antimicrobial resistance to cotrimoxazole, including resistance of Plasmodium species to the closely related antimalarial Fansidar. However, current data actually support a benefit to household contacts of persons receiving cotrimoxazole. Therefore, these concerns remain largely theoretical.
WHO/UNAIDS provisionally recommends cotrimoxazole for all HIV-infected adults with WHO clinical stage 2, 3 or 4 disease or with CD4 counts less than 500 cells/�l.11 For children, WHO/UNAIDS currently recommends cotrimoxazole for all HIV-exposed/ infected infants and older children with HIV-related symptoms or with severe immunosuppression (see companion guidance - Emergency Plan guidance for children aged 0-14 years of age). Updated WHO recommendations on cotrimoxazole prophylaxis were discussed at an international consultation in Geneva in May 2005 and are expected to be released soon. When available, this document will be posted on the OGAC website.
Emergency Plan funds may support:
2. Effective tuberculosis (TB) interventions for HIV-infected persons
TB is a leading cause of severe morbidity and mortality among persons with HIV/AIDS, especially in sub-Saharan Africa where 32 percent of TB patients are HIV-infected;12 and in some areas, the prevalence of HIV infection among TB patients can be as high as 70 percent.13 In sub-Saharan Africa, approximately 39 percent of TB deaths are attributable to HIV.14
HIV-induced immunosupression promotes the development of active TB in persons co-infected with HIV and Mycobacterium tuberculosis,15 and active TB accelerates the progression of HIV disease.16 Therefore, in high HIV prevalence populations, the identification and treatment of active TB are high priorities not only for care of HIV-infected persons but also for control of TB.17 Furthermore, operational research in Africa18 and elsewhere19 has shown that up to 11 percent of HIV-infected persons identified in HIV counseling and testing have undiagnosed TB. Thus, HIV care programs are very likely to include patients with undiagnosed, active TB.
After active TB has been excluded, daily isoniazid (INH) prophylaxis for 6-9 months has been associated with a reduction in the incidence of TB among HIV-infected persons. This effect is most pronounced in persons with a positive tuberculin skin test (TST), in whom a 60 percent reduction in incidence of TB has been observed.20 However, this meta-analysis of seven randomized controlled trials showed that INH preventive therapy (IPT) for 6-12 months given to HIV-infected persons was associated with a 42 percent reduction in TB incidence regardless of TST result. The effect of IPT on mortality is not as clear.
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3. Safe drinking water and personal hygiene
People living in resource-poor settings often have limited access to safe water and basic methods of hygiene and sanitation (e.g. hand washing with soap). Most research on the impact of safe water, sanitation, and hygiene interventions on diarrheal disease has focused on children under 5 years of age because most diarrhea-associated mortality has been associated with this group. Use of a safe water supply was shown to reduce diarrhea by 20 percent in children in a study in Malawi.21 In a review of 144 studies, water treatment and safe storage at the point-of-use (typically the household) were effective in reducing diarrheal prevalence by 26 percent;22 in another review, Gundry et al. estimated a 65 percent reduction in diarrhea from such household-level interventions.23 A study of HIV-infected persons and their families in Uganda showed that use of a simple, home-based safe water system reduced the incidence of diarrheal episodes by 25 percent, the number of days with diarrhea by 33 percent, and the frequency of visible blood or pus in stool.24 The cost of the intervention was less than $5 per family per year. Provision of safe water at the household level in resource-constrained settings is consistent with WHO policies.
A recent review by Curtis showed that hand washing with soap was associated with a 43 percent reduction in diarrheal disease.25 The benefit of hand washing was further supported by a reduction in diarrhea by 62 percent in people in rural Bangladesh,26 and by 53 percent in a randomized controlled trial of children in Pakistan.27 Reviews by Esrey et al. and Huttly et al. of the effect of hygiene promotion interventions on diarrhea morbidity found a median reduction of roughly one-third.22,28 However, the HIV status of the subjects of all of these studies was unknown.
Protecting the water supply by use of latrines has also been associated with a reduction in incidence of diarrheal disease. Latrine construction is currently beyond the scope of PEPFAR funding but should be considered for "wrap-around" support by other funding sources.
Diarrhea incidence, duration, severity, and mortality are all higher in children with HIV/AIDS than in HIV-uninfected children, and chronic diarrhea is also a major cause of morbidity and mortality in HIV-infected adults. Therefore, interventions that reduce diarrheal episodes should be considered for use in all HIV-infected persons.
Emergency Plan funds may support:
4. Insecticide-treated nets
Malaria is a life-threatening parasitic disease transmitted from person-to-person through the bite of a mosquito. The disease exerts its heaviest toll in Africa, where about 90 percent of the more than one million deaths from malaria worldwide occur each year. Prevalence of parasitemia ranges from 22-61 percent in the general population and can be as high as 82 percent in children 5-10 years of age.29 In a study in Uganda, the prevalence of parasitemia and clinical malaria in HIV-infected persons was found to be almost twice that in HIV-uninfected persons.30 In another study, malaria was found to be 1.7-fold more common in HIV-infected children compared to HIV-uninfected children.8 HIV was also associated with more severe manifestations of malaria.31,32
Insecticide-treated nets (ITN) have proven to be effective in reducing the risk of malaria in children living in areas with high transmission: 27.8 percent reduction in malaria parasitemia,33 17 percent reduction in mortality in children under 5 years of age,34 and 25 percent reduction in all-cause mortality in children 1-9 years old.35 In randomized controlled trials in Kenya, bednets reduced symptomatic malaria in children by 52 percent, placental malaria by 35 percent and the prevalence of low birth weight by 28 percent.36,37 ITNs also had a protective effect on persons in nearby homes.38 Mermin et al. recently addressed the effects of ITNs on malaria in HIV-positive persons.39 They found that the combination of co-trimoxazole, antiretroviral therapy, and ITNs substantially reduced the frequency of malaria in adults with HIV. Compared with a baseline malaria incidence of 50.8 episodes per 100 person-years, co-trimoxazole prophylaxis was associated with 9.0 episodes per 100 person-years (adjusted incidence rate ratio [IRR] 0.24, 95% CI 0.15-0.38); ART and co-trimoxazole with 3.5 episodes per 100 person-years (0.08, 0.04-0.17); and co-trimoxazole, ART, and ITNs with 2.1 episodes per 100 person-years (0.05, 0.03-0.08).
The currently recommended bednet is the long-lasting, insecticide-treated net. The insecticide in these nets lasts for 3-5 years - the life of the net. The average cost of an ITN is about $5, making it a low-cost public health intervention.
Emergency Plan funds may support:
USG teams in Emergency Plan countries that are also part of the President�s Malaria Initiative should coordinate closely and use both funding streams creatively to serve HIV-affected individuals in the distribution of (long-lasting) insecticide-impregnated nets. Emergency Plan support can be used for insecticide-treated nets to cover the sleeping areas of households of HIV-infected persons in areas in which malaria is endemic.
5. Nutrition and micronutrient supplementation
Micronutrients, including vitamins, have gained increasing interest as a preventive measure for HIV-infected persons. Several studies have shown positive benefits of daily high-dose multiple micronutrient supplements for HIV-positive adults. In one trial of HIV-infected men and women in Thailand, a daily supplement containing 21 vitamins and minerals was associated with a 47 percent reduction in mortality, primarily among those with CD4 counts <200 who would normally be eligible for HAART, but were not on antiretroviral drugs during this study.40 Multi-vitamins (doses of vitamins B, C, E from 6-23 times the recommended daily allowance) administered to HIV-infected pregnant women reduced fetal death by 39 percent, and decreased the risk of low birth weight (<2500 g) by 44 percent and pre-term birth (<34 weeks gestation) by 39 percent. Multi-vitamins also significantly increased maternal CD4, CD8, and CD3 counts.41 Daily multi-vitamin supplementation improved weight gain among HIV-infected Tanzanian pregnant women.42 In this same trial, daily vitamin A plus beta-carotene was associated with an increased risk of HIV transmission during breastfeeding.43 Extended follow-up of these women revealed that daily multi-vitamin supplementation of high doses of vitamins B, C, E taken during pregnancy and throughout the breastfeeding period reduced progression to WHO clinical stage 4 or death by 29 percent, and resulted in higher CD4 and lower viral load; inclusion of vitamin A plus beta-carotene in the supplement attenuated its benefits.44 WHO has concluded that while these studies are promising, they do not warrant recommending higher daily micronutrient intakes for PLWHAs than those recommended for the general population.
Emergency Plan funds may support:
6. Services and counseling to prevent the transmission of HIV to others
HIV post-test counseling is the first step to introducing HIV-infected persons to appropriate prevention messages, medical care and treatment. Providing test results and appropriate counseling to HIV-infected persons has been shown to decrease high-risk sexual behavior and HIV transmission.45,46 In the Democratic Republic of Congo, condom use among HIV discordant couples increased from 5 percent before counseling to 71 percent after counseling, and a low rate of HIV seroconversion was noted among this group.47 The provision of low-cost condoms has also been associated with an 80 percent reduction in HIV transmission among discordant couples.48 Therefore, counseling HIV-infected persons to refrain from high-risk behaviors offers an opportunity to reduce transmission of HIV to others. It will also reduce the risk to the patient of acquiring additional sexually transmitted infections.
It is important to provide ongoing prevention messages for people with HIV infection to support their maintenance of safe sexual practices using abstinence, being faithful and the correct and consistent use of condoms (ABC). Integrating prevention into care and treatment settings, including provider-delivered risk reduction information, will allow patients to receive routine access to important messages about eliminating, or decreasing frequency of, high-risk behavior.
Emergency Plan funds may support:
7. HIV counseling and testing of family members and other contacts
HIV counseling and testing may also benefit family members and other contacts of HIV-infected persons by facilitating early referral of HIV-infected persons to care and prevention. As indicated above, couples counseling and testing has been demonstrated to be effective in reducing HIV transmission risk among HIV-discordant couples. Counseling and testing models within care programs may include: 1) family-based (including home-based) counseling and testing that encourages HIV counseling and testing of family members, including children; 2) couples counseling and testing in which the partner of the HIV-infected person is counseled and tested; and 3) work site-based counseling and testing.
Emergency Plan funds may support:
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