Global Health Interventions: A Review of the Evidence Background Methodology • Glossary

Overview: HIV/AIDS

Background

The human immunodeficiency virus (HIV) is a retrovirus that causes the acquired immunodeficiency syndrome (AIDS). HIV attacks the immune system, creating vulnerability to a range of deadly opportunistic infections such as tuberculosis. It is transmitted through sexual contact; the use of blood-contaminated syringes, contaminated medical instruments, and blood products; and from women to their infants perinatally or through breast-milk. Average survival after infection is 9 to 11 years.[1] Without treatment, survival following an AIDS diagnosis ranges between 6 and 19 months.[2] Combination antiretroviral therapy (ART) reduces death rates by 80%, and raises the life expectancy following infection to 20 or more years.[3],[4] Certain structural components of the virus evolve during its reproduction within the human body, hampering efforts to generate an effective vaccine. The virus can also develop resistance against ART, particularly with inadequate treatment.

Epidemiology [1]

• Since the beginning of the AIDS epidemic, more than 25 million people have died of HIV-related causes.
• As of 2009, more than 33 million people were living with HIV, including 2.3 million children less than 15 years old or younger.
• In the most heavily affected countries, HIV has reduced life expectancy by more than 20 years, slowed economic growth, and deepened household poverty.
• In 2009 alone, a total of 2.6 million people were newly infected with the HIV virus; including 370,000 children.
• In some heavily affected countries, dramatic changes in sexual behavior have been accompanied by declines in the number of new HIV infections. This contributed to a global stabilization, starting in the late 1990s, in the percentage of people aged 15 - 49 who are infected with HIV.[5]
• In sub-Saharan Africa alone, the epidemic has orphaned nearly 12 million children.
• The annual number of AIDS deaths declined from 2.2 million in 2005 to 1.8 million in 2009, partly due to the substantial increase in access to HIV treatment.

The prevention and treatment intervention assessments below summarize information presented in the "Key Findings" table.

Prevention: What Works?

A wide array of HIV prevention strategies has been assessed, some with strong evidence of benefit and some less clearly so. We classify prevention into six categories: reduce risk from sex through behavioral approaches; reduce risk from sex through biological approaches; reduce risk from needle use; employ structural approaches; and reduce transmission from mother to child (antiretrovirals and other strategies).

• Reduce risk from sex: behavioral approaches. HIV counseling and testing (HCT) does not reliably reduce HIV risk behaviors for HIV-uninfected persons, but does appear to do so for HIV-positive persons and sero-discordant couples by 32-56% (very weak evidence). A Cochrane systematic review for efficacy of couples-based counseling and testing is expected in late 2010 or early 2011. Peer education reduces HIV transmission by 68% (confidence interval [CI] 34-85%, very weak evidence) and risk behaviors by 48% (CI 37-57%, strong evidence). Behavioral interventions for women may reduce HIV incidence (0 – 36% inter-quartile range, very weak evidence, only three of 11 studies had statistically significant results). Behavioral interventions for youth do not decrease HIV incidence, but do appear to reduce non-use of condoms by 22-71% (moderate strength evidence). Evidence for delayed sexual onset shows no pattern (not in table). Mass media has mixed results; combined with interpersonal communication it led to lower HIV incidence in one study. Finally, condom social marketing has mixed results, with a low magnitude benefit in most studies (weak evidence).
• Reduce risk from sex: biological approaches. Circumcision of adult males is 50-54% effective in reducing HIV transmission to males, based on three RCTs (very strong evidence). STI treatment has been examined in eight studies, with one statistically significant reduction in HIV incidence and a wide confidence interval (-17 – 20%), and lower STIs and risk behaviors (16-23%, moderate strength evidence). Nonoxynol-9 and microbicides have failed to reduce HIV incidence. One RCT (CAPRISA) of a microbicide containing an antiretroviral drug found a 37% (CI 5-58%) reduction in HIV incidence, and one RCT (VOICE) of a similar microbicide was stopped in November 2011 due to lack of efficacy (two well-done RCT with mixed results, weak evidence). Vaccines have not worked (-32 - 16%), nor has the latex diaphragm. Pre-exposure prophylaxis with the antiretroviral combination tenofovir plus emtricitabine (TDF/FTC) has reduced HIV transmission in three RCTs, by 44% (15 - 63%) in MSMs in the U.S., 73% (49 – 85%) in discordant couples in Kenya and Uganda, and 62% (22 – 83%) in men and women in Botswana (very strong evidence). Two other trials found no effect, one due to low sample size and one still being assessed. Antiretroviral therapy (ART) reduced HIV incidence by 96% (73 - 99%) in discordant couples in African in a large RCT, with similar results from several earlier non-RCTs (strong evidence).
• Reduce risk from needle/syringe use. Providing clean needles has unclear evidence for HIV incidence, but appears to reduce needle sharing by 52-62% (weak evidence, due to reliance on pre-post and cross-sectional studies instead of RCTs). Peer education reduces needle sharing by 63% (CI 33-80%, weak evidence). Methadone maintenance reduces risk by 13-63% (or more, from multiple types of risk reduction; moderate strength evidence).
• Structural approaches. Structural interventions to reduce HIV cover a wide range of potential strategies, with as yet unsettled definitions and little empirical evidence. One study of microfinance found no benefit (with wide confidence intervals). According to a preliminary report, a study in Malawi found that conditional or unconditional cash transfers to girls 13-22 years old was associated with lower HIV prevalence.[7]
• Reduce transmission from mother to child: Antiretroviral drug prophylaxis during the antenatal and perinatal period is among the most effective preventive strategies. Comparing any antiretroviral therapy with placebo, reduction in transmission ranges from 22-36% in breast-fed infants (moderately strong evidence), to 35-97% in non-breast-fed infants (weak evidence). Strong evidence suggests that compared with placebo, zidovudine regimens reduce infant mortality by 54-69% and perinatal HIV incidence by 31-58% (very strong evidence). For perinatal regimens, nevirapine appears better than zidovudine (28-42%, weak evidence). Longer regimens appear more effective than shorter regimens for non-breast fed infants (24-45%, weak evidence) but not significantly so for breast-fed infants. 
• Reduce transmission from mother to child: other approaches. Very strong evidence indicates that both vitamin A and vaginal disinfection are ineffective in reducing transmission to infants. Caesarean section appears highly effective in reducing transmission (83%, weak evidence), however is impractical or unsafe in many settings.

Treatment: What Works?

An extraordinary treatment armamentarium has been developed for HIV, with transformative advances in therapeutic efficacy, convenience, and pricing. We examine treatment in three categories: antiretroviral therapy (ART), antimicrobials, and nutritional interventions.

• Antiretroviral therapy (ART). The high efficacy (80% or greater) of combination ART in reducing HIV disease progression and opportunistic infections is widely accepted. Thus, we focus on comparisons relevant to current policy decisions. For example, variations on the composition of first-line ART regimens did not have a statistically significant effect treatment failure or viral load (moderately strong evidence). However, WHO recommends tenofovir-containing first line regimens due to lower risks and ease of administration.[8] Early initiation of ART is associated with a 74% reduction in mortality (CI 38-89%, moderate strength of evidence). Directly observed administration of ARV drugs may reduce mortality (8 – 33%, not statistically significant despite very strong evidence) and has no benefit for viral load. Monitoring with CD4 testing reduces mortality by 26% (CI 11-39%, strong evidence) and opportunistic infections by a similar amount. Adding viral load monitoring does not appear to increase benefit.
• Antimicrobial agents. Cotrimoxazole (bactrim, a very inexpensive drug) reduces mortality by 31-37% (very strong evidence) and hospitalizations or serious morbid events by 23-34% (moderately strong evidence). Anti-fungal agents reduce the incidence of invasive cryptococcal disease by 79% (CI 54-91% very strong evidence), but apparently not mortality. The anti-fungal agent fluconazole reduces clinical episodes of oral candidiasis by 39-84% (very strong evidence). Isoniazid is effective in reducing TB mortality in HIV-infected children (54%, CI 6-78%), and TB incidence by 72% (CI 23-90%), both with weak evidence.
• Nutritional supplements. Administration of vitamin A appears to reduce mortality in HIV-infected children by 63% (CI 16 – 83%, weak evidence) and perhaps also morbidity. Other micronutrients reduce mortality by 50-67% (weak evidence). Multivitamins for pregnant and lactating mothers reduce mortality in infants and mothers and disease progression by 7 – 29% (moderately strong evidence, only four of 9 studies statistically significant).

Summary/Future Directions

Prevention. The most effective prevention strategies, based on evidence of reduction in HIV incidence and risk behaviors, appear to be adult male circumcision; ARVs for mother to child transmission and adult to adult transmission (both PrEP for uninfected individuals and ART for infected individuals); and peer education. An ARV-containing microbicide was found in a recent RCT to reduce HIV incidence, but another study was stopped due to lack of efficacy. Strategies with evidence of behavioral risk reduction include counseling and testing for persons who test HIV+ (with a pending review of couples counseling), methadone maintenance and clean needles for IDUs, female condoms, and behavioral interventions for youth. Condom social marketing and mass media have worked in some studies.

Treatment. Antiretroviral therapy is highly effective, with evidence of important clinical and prevention benefit from initiation ea rlier in disease (with higher CD4 counts). Other antimicrobials and micro-nutrients provide important additional clinical benefit.

Future directions depend on programmatic emphasis as well as continued research on vaccines. Over the last decade, the international response to the HIV epidemic has emphasized access to ART. More recently, consensus is converging on how to contain and mitigate the epidemic going forward. One understanding is that universal access to treatment will be difficult to attain and finance unless incidence is dramatically reduced. The availability of treatment means that effective prevention will lead to large savings in life-long ART costs. The second understanding is that some of the major pillars of global HIV prevention are based on weak evidence (eg, VCT) or cannot have a large impact on HIV epidemic patterns (pMTCT). These linked understandings have led to a renewed commitment to evidence-based spending on prevention. Adult male circumcision has emerged as an effective, cost-effective and acceptable intervention in many developing-countries. It can in many settings provide the core of a revitalized prevention effort. Other key components of prevention are HCT, condom social marketing, peer interventions in high risk groups, and youth interventions. In addition, confirmatory evidence of the efficacy of ARV-containing microbicides would significantly enhance the prevention toolkit. ART as treatment and PrEP contribute importantly to prevention. The optimal combination is likely to depend on the local epidemic and social context, as well as cost and cost-effectiveness.

Improved efficiencies for ART programming will be essential. Attention will focus on methods to increase and stretch limited resources. The use of lower cadre staff to perform tasks traditionally assigned to physicians will be common, and require evaluation. The scale-up of ART implies that hundreds of thousands of patients will eventually fail first-line therapies and require 3-5 times more costly protease inhibitor-based second-line regimens. Further price declines for these drugs will be essential.

An effective vaccine would further transform control efforts. By the late 1990s the failure of traditional vaccine approaches typified by antigen-based candidates prompted the development of vaccines intended to elicit cell-mediated immune (CMI) responses. Although there are 30 CMI vaccines in development, the 2007 failure of a promising candidate prompted new approaches, including vaccines intended to elicit both CMI and antibody-based immune responses.[9] The field has experienced major set-backs and the technical challenges remain severe. However, the public health rewards of an effective vaccine could be enormous. Funders such as US National Institute of Allergy and Infectious Diseases and the Bill and Melinda Gates Foundation continue to provide substantial support for vaccine development, particularly for innovative and collaborative efforts.

References

1. UNAIDS. Report on the Global AIDS Epidemic 2010. Available from: http://www.unaids.org/GlobalReport/default.htm.

2. Zwahlen M, Egger M. Progression and mortality of untreated HIV-positive individuals living in resource-limited settings: Update of literature review and evidence synthesis. UNAIDS, 2006. Available from:  http://data.unaids.org/pub/periodical/2006/zwahlen_unaids_hq_05_422204_2007_en.pdf

3. Knoll B, Lassmann B, Temesgen Z. Current status of HIV infection: a review for non-HIV-treating physicians. Int J Dermatol. 2007 Dec; 46 (12): 1219–28.

4. Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet. 2008 Jul 26; 372 (9635): 293–9.

5. UNAIDS. Report on the Global AIDS Epidemic 2008. Available from: http://www.unaids.org/en/dataanalysis/epidemiology/2008reportontheglobalaidsepidemic/

6. Gupta GR, Parkhurst JO, Ogden JA, Aggleton P, Mahal A. Structural approaches to HIV prevention. Lancet. 2008 Aug 30;372(9640):764-75. Epub 2008 Aug 5.

7. The World Bank. Malawi and Tanzania Research Shows Promise in Preventing HIV and Sexually-Transmitted Infections. 2010, July 18. Available from: http://go.worldbank.org/BX0O3N4F10.

8. WHO. Rapid advice: antiretroviral therapy for HIV infection in adults and adolescents. November 2009. Available from: http://www.who.int/hiv/pub/arv/advice/en/index.html.

9. IAVI. History of AIDS Vaccine Efforts. 2010. Available from: http://www.iavi.org/research-development/Pages/state-of-field.aspx.

-- Updated June 2011