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RHO archives : Topics : HIV/AIDS

Annotated Bibliography

This is page 3 of the HIV/AIDS Annotated Bibliography. This page contains:

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Opportunistic infections and co-infections

Abularch, S. and Anderson, J. Gynecologic problems. In: A Guide to the Clinical Care of Women with HIV. J.R. Anderson, Ed. Rockville, Maryland: U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau (2001). Available at: www.hab.hrsa.gov/womencare.htm.
While women are susceptible to the same opportunistic infections as men, they face the additional risk of gynecologic infections and cancers. This chapter uses a problem-oriented approach to examine the most common gynecologic complaints, discussing their various diagnosis, evaluation, management, and relationship to HIV. Topics include abnormal bleeding, abnormal pap smears, genital ulcers, vaginal discharge, pelvic/abdominal pain, pelvic mass, urinary symptoms, genital warts, genital masses/nodules, genital itching/irritation, breast lumps, menopause, health-maintenance issues, and guidelines for gynecological referral.

Chaisson, R. et al. Impact of opportunistic disease on survival in patients with HIV infection. AIDS 12(1):29–33 (1998).
The goal of this study was to assess the impact of opportunistic illnesses on survival in AIDS patients. A total of 2081 AIDS patients were followed for a mean of 30 months. 35 percent of the patients died during the follow up. The following opportunistic illnesses were found to be significantly associated with death, independently of CD4 cell count: Pneumocystis carinii pneumonia (PCP), cytomegalovirus (CMV) disease, Mycobacterium avium complex (MAC) disease, Candida esophagitis, Kaposi's sarcoma, lymphoma, progressive multifocal leukoencephalopathy (PML), dementia, wasting, toxoplasmosis, and crystosporidiosis. Cryptococcosis and herpes zoster were not found to be associated with death. The researchers concluded that most opportunistic illnesses increase the risk of death among AIDS patients independently of CD4 cell count.

Corbett, E. et al. HIV/AIDS and the control of other infectious diseases in Africa. Lancet 359(9324):2177–2187 (June 22, 2002).
This review examines the relationship in Africa between HIV-1 and three other infectious diseases: malaria, sexually transmitted diseases (STDs) and tuberculosis. Research has shown that malaria infection occurs more frequently and with higher parasite density in HIV-1-positive pregnant women than in their HIV-negative counterparts. Malaria in pregnant HIV-infected women may lead to higher rate of infant mortality, but the causes are not yet clear. The presence of other STDs, particular ulcerative varieties such as chanchroid, syphilis and herpes, is believed to enhance HIV-1 transmission by compromising mucosal integrity. Improved management of STDs is essential to control of HIV-1 transmission. Research also suggests that the presence of HIV-1 amplifies the risk of reactivating latent tuberculosis infection and of a rapid progression of tubercular disease. Public-health efforts in Africa should include both increased HIV-1 prevention and care programs and augmented measures to control and treat other infectious diseases.

Feikin D, Feldman C, Shuchat A, et al. Global strategies to prevent bacterial pneumonia in adults with HIV disease. The Lancet Infectious Diseases. 2004;4(7):445–455.
This article was based on a review of literature dealing with prevention and management of bacterial pneumonia among HIV-infected adults. Rates of bacterial pneumonia increase approximately 100-fold during acute HIV infection. Increased risk of pneumonia occurs among HIV-positive people who inject drugs, or smoke cocaine, crack, marijuana, or cigarettes. Alcoholism, cirrhosis, low albumin, asthma, and sickle cell disease constitute further risks for bacterial pneumonia among people living with HIV/AIDS. Strategies for preventing bacterial pneumonia in HIV-infected persons include antimicrobial prophylaxis and vaccination with polysaccharide. Antiretroviral therapy for HIV infection also appears to reduce the risk of bacterial pneumonia. The authors recommend increased efforts to prevent bacterial pneumonia in people living with HIV/AIDS.

Friedland G et al. Utility of tuberculosis directly observed therapy programs as sites for access to and provision of antiretroviral therapy in resource-limited countries. Clinical Infectious Diseases. 2004;38(Suppl 5):421–428.
Tuberculosis is the principal cause of illness and death in people living with HIV/AIDS worldwide. This article examines the possibility of integrating antiretroviral therapy for HIV infection into existing directly observed therapy programs to treat tuberculosis. Challenges to this strategy include program and infrastructure development, patient confidentiality, side effects and toxicities, pharmacological issues (interactions between drug therapy for HIV and tuberculosis), immune system reactions, and durability of benefits. The authors maintain that introducing antiretroviral therapy into directly observed treatment programs for tuberculosis can be “safe and effective.”

Holmes, C. et al. Review of human immunodeficiency virus type 1-related opportunistic infections in sub-Saharan Africa. Clinical Infectious Diseases 36:652–662 (March 2003).
The authors of this article set out to broaden understanding of the natural history of HIV-1 and opportunistic infections in sub-Saharan Africa, with the goal of optimizing strategies for the prophylaxis and treatment of opportunistic infections and understanding the probable impact of antiretroviral therapy. A literature search indicated that tuberculosis, bacterial infections, and malaria are the principal causes of HIV-related illness in sub-Saharan Africa. The authors maintain that efforts to administer antiretroviral therapy in Africa should be accompanied by prophylaxis for opportunistic infections, as a strategy to prevent HIV-related illness and death.

Maartens, G. Opportunistic infections associated with HIV infection in Africa. Oral Diseases 8 (Suppl. 2) (2002).
Given the unavailability of antiretrovirals for most people living with HIV/AIDS in Africa, opportunistic infections occur at a much higher rate than in the developed world. Tuberculosis is the most common cause of illness and death in those infected with HIV. Other opportunistic infections occurring frequently in HIV-positive Africans include pneumococcal infections and diarrhea, which is aggravated by lack of access to safe water. The author recommends primary prevention for opportunistic infections in Africa.

PATH (Program for Appropriate Technology in Health). Tuberculosis: A global health emergency. Outlook 17(3) (November 1999). Available at: www.path.org/outlook/html/17_3.htm).
This article reviews the epidemiology of tuberculosis, including the role of HIV, the social and economic impact of tuberculosis, with a focus on the impact on women. It also discusses current strategies and lessons learned from efforts to strengthen tuberculosis control activities.

Rockstroh J, Spengler U. HIV and hepatitis C virus co-infection. Lancet Infectious Diseases. 2004;4(7):437–444.
Liver disease linked to chronic hepatitis C infection is becoming an increasingly common source of illness and death among people living with HIV/AIDS, particularly in more advanced stages of HIV. Worldwide, 60 to 180 million people are believed to be infected with hepatitis C virus (HCV), which is ten times as infectious as HIV. Higher levels of HCV are present in HIV-positive people than in HIV-negative individuals. Treatment with a combination of pegylated interferon and ribavirin has achieved success in reducing the level of HCV in people living with HIV/AIDS. However, not all HIV-infected people respond to the combination therapy and more effective treatment for HIV/HCV co-infection is an important goal for the future.

Thio, C. Treatment of chronic hepatitis B in the HIV-infected patient. Hopkins HIV Report 15(4):9 (July 2003).
Chronic hepatitis B infection (CHB) is a serious problem for people living with HIV/AIDS, up to 10 percent of whom are co-infected with CHB. In addition to the risk of infection with hepatitis A and hepatitis C in people with CHB, HIV infection can lead to cirrhosis and liver-related death. Co-infected individuals should also minimize or eliminate alcohol consumption. Current guidelines suggest that the following co-infected individuals seek treatment for chronic hepatitis B infection: those with detectable hepatitis B surface antigen for longer than six months; those in whom there is evidence of viral replication demonstrated by hepatitis B virus DNA of greater than 105 c/mL or hepatitis B e antigen in serum; and those in whom there is evidence of necroinflammation observed through a liver biopsy or persistent elevation in ALT. Treatment options for CHB in HIV-infected people include interferon-alpha (through subcutaneous injections administered three times per week); lamivudine in a daily dose of 150 mg bid or 300 mg qd; and adefovir dipivoxil (10 mg daily) or tenofovir (300 mg per day), in the case of lamivudine-resistant hepatitis B. The author suggests that combination therapy may be the most effective treatment for HIV/hepatitis B co-infected patients in the future.

UNAIDS. HIV-Related Opportunistic Diseases. UNAIDS Technical Update. Geneva: UNAIDS (October 1998). Available at: www.unaids.org/publications/documents/impact/opportunistic/opportue.pdf. This document provides an overview of the most common HIV-related opportunistic infections. These include bacterial diseases, protozoal diseases, fungal diseases, viral diseases, and HIV-associated malignancies. The worldwide distribution of these diseases varies widely, even among developing countries. For example, in Mexico 30 to 43 percent of people living with HIV/AIDS suffer from Kaposi's sarcoma, whereas in Brazil only 5 percent do. In Cote dIvoire, 54 percent percent of people living with HIV/AIDS suffer from tuberculosis, while only 20 percent of those in Thailand do. Costs for treatment likewise vary widely. Effective intervention against opportunistic diseases requires not only access to appropriate medication, but also an infrastructure that can support diagnosis, treatment, monitoring, and counseling of patients. Challenges to providing treatment are lack of advocacy, infrastructure, and information. Responses to the problem include prevention, mobilizing community-based groups, and prioritizing public funding.

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Drugs and treatment for HIV/AIDS

Cooper DA, Lange JM. Peptide inhibitors of virus-cell fusion: enfuvirtide as a case study in clinical discovery and development. Lancet Infectious Diseases. 2004;4(7):426–436.
Enfuvirtide, a peptidic antiretroviral, is the first clinically approved antiviral fusion inhibitor, as well as the first antiretroviral administered parenterally rather than ingested. Enfuvirtide has proven effective at controlling viral load, and has a low potential for systemic toxicities. Tests showed that enfuvirtide “significantly improves medical outcomes in highly treatment-experienced patients with HIV-1 infection.” In phase II studies, patients who had been taking the drug for nearly a year “stated that they would choose to continue enfuvirtide if offered, with patient perception of effectiveness and lack of side-effects being the most common reasons.”

Farmer, P. et al. Community-based approaches to HIV treatment in resource-poor settings. Lancet 358(9279): 404-409 (August 4, 2001).
This article describes Clinique Bon Sauveur, a clinic in a resource-poor, rural Haitian community that has been providing HAART treatment to people living with AIDS since late 1998. The treatment program employs the preexisting tuberculosis-control infrastructure to provide direct observation therapy (DOT) of HAART to people living with AIDS. DOT provides every patient with an accompagnateur who observes the ingestion of pills and provides moral support to the patient and family. The clinic also provides social support to patients in the form of monthly meetings and assistance with childrens school fees. Patients rarely experienced side effects and have been far less likely to require admission to hospital than untreated HIV-positive patients. Under the DOT system the complexity of the regimens has been manageable and adherence is high. Using the example of Clinique Bon Sauveur, the article argues that HAART treatment is feasible in poor rural areas without strong preexisting health infrastructures.

Fawzi W et al. A randomized trial of multivitamin supplements and HIV disease progression and mortality. New England Journal of Medicine. 2004;351(1):23–32.
In this article, the authors analyze the results of a double-blind, placebo-controlled trial conducted in Dar es Salaam, Tanzania, in which HIV-infected pregnant women received either a multivitamin supplement (vitamins B, C, and E), a multivitamin supplement with vitamin A, vitamin A alone, or a placebo. Multivitamins “significantly reduced oral and gastrointestinal manifestations of HIV disease” and slowed the progression to advanced illness, while vitamin A alone, the addition of vitamin A, and placebos had no discernible effect on illness or disease progression. Multivitamins also led to significant reductions in oral ulcers, angular cheilitis, difficult or painful swallowing, dysentery, and fatigue. The authors recommend the use of multivitamins where antiretrovirals are unavailable or to preserve the use of antiretrovirals for more advanced stages of illness.

Floyd, K. et al. Cost and Financing Aspects of Providing Anti-Retroviral Therapy: A Background Paper. The World Bank (1998). Available at: www.worldbank.org/aids-econ/arv/floyd/index.htm)
The economic aspects of providing HIV-infected people with antiretroviral therapy (zidovudine) in scarce-resource settings are discussed. The author concludes that antiretroviral therapy is costly in scarce-resource settings and appears not to be cost-effective. However, it may become more affordable in time "as bulk-purchase arrangements become more commonplace, and as partnerships are established among international agencies, governments and drug companies." 

Harries, A. et al. Highly active antiretroviral therapy and tuberculosis control in Africa: synergies and potential. Bulletin of the World Health Organization 80(6):464–470 (2002).
This article maintains that there is a need to develop strategies to control tuberculosis and HIV simultaneously. Active case-finding may help to detect tuberculosis infections in such places as prisons, boarding schools, health-care institutions and the households of diagnosed tuberculosis patients. Providing a package of care for HIV-related illness (including psychosocial support, screening for tuberculosis and STIs, clinical care for opportunistic infections, palliative care for terminal illness, prevention of mother-to-child HIV transmission, home-based care, preventive therapy, and the possibility of antiretroviral drugs) could also help. The best approach may be to deliver highly active antiretroviral therapy within a comprehensive HIV/AIDS management strategy.

Individual Members of the Faculty of Harvard Universities. Consensus Statement on Antiretroviral Treatment for AIDS in Poor Countries. (April 2001). Available at: www.hsph.harvard.edu.
Developing methods to provide treatment to the worlds 36 million people living with HIV/AIDS should be a global health priority. There are four compelling reasons to provide HIV/AIDS prevention and treatment: First, to save and prolong the lives of people living with AIDS; second, to optimize prevention efforts by giving people an incentive to be tested and by lowering the viral-load of those already infected, thus preventing transmission; third, to reduce the number of children who are orphaned every year due to AIDS and thus prevent a demographic shift that will result in a higher number of teenagers than adults by 2020, causing further political instability; finally, treatment will reduce the rate of deaths among skilled workers in developing countries and thus help to continue economic development. Objections to the provision of HIV/AIDS treatment in poor countries include the inadequate medical infrastructure, difficulties with adherence to complicated medical regimens, the high cost of antiretroviral drugs, and the insufficient commitment of political leaders. These objections are not sufficiently persuasive. Treatment of HIV infection in poor countries is feasible, affordable, and effective if several strategies are employed. First, existing infrastructures can be used for initial pilot programs and countrywide trials; infrastructures can later be supplemented. Second, simplified HAART regimens should be used in addition to DOT to eliminate the development of drug resistance. Third, a fund will be established to cover the costs of treatment, to which the worlds wealthiest countries will contribute approximately .01 percent of their GNP. Finally, an HIV/AIDS Prevention and Treatment Trust Fund should be established that relies on wealthy countries for financial and scientific leadership and poor countries for political and institutional support at national and community levels.

Kober K, Van Damme W. Scaling up access to antiretroviral treatment in southern Africa: who will do the job? Lancet. 2004;364(9428):103–107.
The authors visited Malawi, Mozambique, Swaziland, and South Africa—countries with some of the highest levels of HIV infection in the world—to observe the effects of HIV/AIDS, particularly on health systems, and to examine the principal issues linked to expanding antiretroviral treatment for HIV infection. The main finding was that human rather than financial resources are perceived as the main obstacle to implementing antiretroviral treatment. The authors recommend increasing the number of health workers, entrusting the administration of antiretroviral programs to clinical officers and nurses, and enlisting literate, educated HIV-positive people to help administer treatment programs.

Kumarasamy N. et al. Monitoring HIV treatment in the developing world. Lancet Infectious Diseases 2(11): 656–657 (November 2002).
The authors of this short reflection underscore the opportunity created by the availability of highly active antiretroviral therapy in India and parts of Africa for less than US$400 per year. This positive development contrasts with the continued high cost of monitoring antiretroviral therapy using CD4 count testing and HIV plasma viral load (PVL): over US$1,000 per year. "HIV PVL testing is based on patent-protected nucleic acid amplification techniques … while CD4 count testing is quite complex, requiring expensive equipment and reagents." Possible solutions to the problem include simple, inexpensive laboratory measures using hemoglobin and the total lymphocyte count; CD4-count enumeration using Dynabeads ("magetic polymer spheres designed to rapidly and efficiently bind specific target molecules"); and the measurement of p24 antigen as a surrogate for plasma HIV-RNA viral load.

The PLATO Collaboration. Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes. Lancet. 2004;364(9428):51–62.
Despite the existence and availability of multiple combination-drug strategies to treat HIV infection, some patients do not respond to any of the major classes of antiretroviral drugs (nucleoside reverse-transcriptase inhibitors, protease inhibitors, and non-nucleoside reverse-transcriptase inhibitors). The authors of this article studied data from 13 sources in Australia, Europe, and North America, representing 15,214 patients, 2,577 of whom exhibited failure to all three classes of antiretroviral drugs. Based on the data supplied, the authors concluded that the current CD4-cell count rather than the current viral load determines the short-term risk of death in such patients. The recommendation is therefore to maintain as high a CD4-cell count for as long as possible.

Rosenberg, T. Look at Brazil. New York Times Magazine (January 28, 2001).
In 1997 Brazil began providing its citizens with free access to antiretroviral drugs for the treatment of HIV/AIDS. Since then, the rate of AIDS-related deaths in Brazil has been cut in half, the transmission rate has dropped, and the healthcare system has been stabilized. The costs of providing treatment have been offset by the decreased healthcare costs. For example, between 1997 and 1999 AIDS-related hospitalizations were cut by three-quarters and the Ministry of Health saved an estimated US$422 million. In 1998 Brazil began manufacturing generic copies of patented AIDS drugs, causing drug costs to fall by an average of 79 percent. Brazil is a member of the World Trade Organization, which requires its member states to recognize medical patents. There is a provision in this requirement, however, that allows countries to either make or import generic drugs in times of national emergency. This is called "compulsory licensing" and it requires the country to pay a small royalty to the patent holder. Along with producing its own drugs using the compulsory licensing provision, Brazil has been successful in bargaining with pharmaceutical companies for lower prices on certain drugs. Brazils strong governmental leadership and this leaderships commitment to addressing the HIV/AIDS crisis are the key to its success.

Rosenfield, A. and Yanda, K. AIDS treatment and maternal mortality in resource-poor countries. Journal of the American Medical Women's Association 57(3):167–168 (Summer 2002).
This brief article argues that treatment of AIDS must prioritize womens health, not just those of the children they carry. As the mainstays of families and communities, women deserve both recognition of their value and the right to health care. One new initiative, called "MTCT-Plus," plans to offer women and their children comprehensive care following delivery, including prophylactic drugs to control opportunistic infections, and, where, possible, antiretroviral drugs.

Sethi A. Adherence and HIV drug resistance. The Hopkins HIV Report. 2004;16(1):6–8.
In this article, the author examines studies suggesting that there is a “bell-shaped” relationship between adherence and resistance. Under this hypothesis, “the greatest risk of drug resistance results from only marginally sub-optimal adherence.” A study conducted at the Johns Hopkins Moore Clinic among patients receiving HAART revealed that adherence of 70 to 89 percent more than tripled the risk of drug mutation as compared to patient adherence of less than 70 percent or more than 90 percent. These findings present a challenge to HIV clinicians, who must counsel patients to adhere as closely as possible to their HAART regimen, with the knowledge that low levels of adherence may be less dangerous than medium adherence to the regimen. At the same time, “even perfect adherence may not prevent resistance,” while non-adherence “is associated with virologic failure, immunologic failure, and clinical disease progression.”

World Health Organization (WHO). WHO takes major steps to make HIV treatment accessible: treatment guidelines and AIDS medicines list announced by WHO [press release]. (April 22, 2002). Available online in English (www.who.int/inf/en/pr-2002-28.html) and French (www.who.int/inf/fr/cp-2002-28.html).
This announcement from WHO summarizes their effort to make HIV treatment accessible to at least 3 million people in developing countries by 2005. Information about the treatment guidelines and the Essentials Medicines List are available on WHO's website (www.who.int/medicines/).

World Trade Organization (WTO). Declaration on the TRIPS Agreement and Public Health, Adopted 14 November 2001. (November 20, 2001). Available from the Documents online database of the WTO website, at: http://docsonline.wto.org/gen_home.asp?language=1&_=1.
This is the WTO ministerial-approved clarification on the Trade-Related Aspects of Intellectual Property Rights (TRIPS Agreement). It states "We recognize the gravity of the public health problems afflicting many developing and least-developed countries, especially those resulting from HIV/AIDS, Tuberculosis, malaria, and other epidemics.while reiterating our commitment to the TRIPS Agreement, we affirm that the Agreement can and should be interpreted and implemented in a manner supportive of WTO Members right to protect public health and, in particular, to promote access to medicines for allEach Member has the right to determine what constitutes a national emergency" The agreement thus reaffirms the legitimacy of compulsory licensing. However, it goes on to allow that, "WTO Members with insufficient or no manufacturing capacities in the pharmaceutical sector could face difficulties in making effective use of compulsory licensing under the TRIPS Agreement."

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The role of RTIs in HIV transmission

Dallabetta, G. and Feinberg, M. Efforts to control sexually transmitted diseases as a means to limit HIV transmission: Pros and cons. Current Infectious Diseases Report 3(3):162–168 (April 3, 2001).
A large body of literature suggests that treatment of STIs has a measurable effect on reducing HIV infectiousness and susceptibility at both the individual- and general-population levels. Recent research includes biological studies on genital herpes and genital shedding of HIV-1; two large-scale, community-based clinical trials in Africa, and the use of mathematical modeling to further explore data from these landmark trials. These studies suggest that a combination of improved STI services, syndromic management, and periodic mass treatment tailored to the dynamics of the HIV/AIDS/STI epidemic in a given population can help reduce overall HIV transmission.

Ghys, P. et al. Effect of interventions to control sexually transmitted disease on the incidence of HIV infection in female sex workers. AIDS 15:1421–1431 (2001).
This article presents the findings of a study conducted in Abidjan, Côte dIvoire, from June 1994 to November 1997 in an HIV/STD screening facility for female sex workers. Consenting participants in the intervention were interviewed, clinically examined, screened and tested for STDs, and counseled and tested for HIV infection. Participants then reported once a month to a confidential clinic where they received health education, condoms and STD treatment, as necessary. The women were randomly assigned either to a basic STD diagnosis and treatment strategy or to an intensive strategy that included a gynecologic examination regardless of symptoms. An outcome assessment was conducted every six months and included a gynecologic examination, HIV testing and laboratory tests for STDs. Of the 542 women participating in the study, 225 underwent at least one outcome assessment. The HIV-1 seroincidence rate for participants was considerably lower during the study (6.5 per 100 person-years) than before the study (16.3 per 100 person-years). The HIV-1 seroincidence rate during the study was somewhat lower in the intensive strategy (5.3 per 100 person-years) than in the basic strategy (7.6 per 100 person-years). The authors conclude that national AIDS control programs should consider incorporating into their policy the type of integrated approach for HIV prevention in female sex workers employed in this study.

Grosskurth, H. et al. Impact of improved treatment of sexually transmitted diseases on HIV infection in rural Tanzania: randomised controlled trial. Lancet 26;346(8974):530–536 (August 1995).
The goal of this randomized study was to evaluate the impact of improved STI case management at the primary health care level on the incidence of HIV infection in rural Tanzania. A total of 11,632 cases of STIs were treated at the study health units. Key components of the STI intervention program included establishing an STI reference clinic and laboratory, training health staff in STI syndromic management, supplying STI drugs, and providing health education about STIs. The results showed a 1.2 percent seroconversion rate in the intervention cohort compared to 1.9 percent in the control cohort over two years of follow-up. The largest impact was seen in women aged 15–24 and men aged 25–34. The authors concluded that the 42 percent reduction in HIV incidence over the two-year study period was most likely due to the shortened average duration of STI infection. This study is the first randomized trial to demonstrate the preventive effect of STI treatment on HIV incidence.

Grosskurth, H. et al. Control of sexually transmitted diseases for HIV-1 prevention: understanding the implications of the Mwanza and Rakai trials. Lancet 355(9219):1981–1987 (June 3, 2000).
This article discusses the contrasting results obtained through two randomized, controlled trials of STI treatment for the prevention of HIV-1 infection, in Mwanza, Tanzania, and Rakai, Uganda. Improved STI case management was associated with a decrease in HIV-1 incidence in Mwanza, but not with STI mass treatment in Rakai. Some reductions in curable STIs were seen in both studies. These trials tested different interventions in different HIV-1 epidemic settings and used different evaluation methods; the divergent results may be complementary rather than contradictory. Possible explanations include differences in stage of the HIV-1 epidemic, which can influence exposure to HIV-1 and the distribution of viral load in the infected population; potential differences in the prevalence of incurable STIs (such as genital herpes); perhaps greater importance of symptomatic than symptomless STIs for HIV-1 transmission; and possibly greater effectiveness of continuously available services than of intermittent mass-treatment to control rapid STI reinfection. The authors discuss implications of the trials for policy and future research agendas.

Levine, A. HIV disease in women. Clinical Care Options for HIV, Continuum of Care Series, 9 (October 1998).
This article, available on-line, discusses issues pertaining to HIV/AIDS and women. Topics covered include: sexual transmission of HIV to women, clinical manifestations of HIV disease in women, AIDS-defining conditions in women, gynecologic issues and menstrual abnormalities in HIV-infected women, and cervical cancer and cervical intra-epthelial neoplasia.

Lynn W, Lightman S. Syphilis and HIV: a dangerous combination. Lancet Infectious Diseases. 2004;4(7):456–466.
Syphilis, which causes both genital ulcers and ulcers of the mucous membrane (e.g., inside the mouth) facilitates HIV transmission, while HIV infection can also aggravate the symptoms of syphilis. According to WHO estimates, 349 million people are currently infected with a treatable sexually transmitted infection, with approximately 12 million people acquiring syphilis each year. Syphilis can also cause disease in bones and joints, the central nervous system, and the eyes. A single dose of intramuscular benzathine penicillin can be used to treat primary or secondary syphilis disease, but stronger treatment may be required to treat syphilis in people co-infected with HIV. The authors recommend counseling all people with syphilis about safer sexual practices, more intensive research on developing a vaccine for syphilis, and a concerted public health drive to reduce syphilis transmission.

MacDonald, S. R. et al. Human immunodeficiency virus infection and women: A survey of missed opportunities for testing and diagnosis. American Journal of Obstetrics and Gynecology 178(6):1264–1271 (June 1998).
The goal of this observational study was to examine the factors that prompted testing of women with HIV infection and to evaluate missed opportunities for diagnosis. A missed opportunity for HIV testing was defined as an encounter with a health care provider for prenatal care or any other reproductive health concern regardless of patient risk factors or a health care contact with any patient engaging in high-risk behavior (e.g., illegal injecting drug use, unprotected sexual contact with an HIV-infected or at-risk partner) where HIV testing was not performed. A total of 81 HIV-infected women participated in the study and completed the interviewer-administered survey. Results showed that 65 women (80%) had at least one documented missed opportunity during the 12 months before their diagnosis. There were fewer missed opportunities occurred at pregnancy-related visits compared with other reproductive or nonreproductive health visits. Still, 12 out of 25 women pregnant in the year before their diagnosis failed to be diagnosed during that pregnancy. The researchers emphasized the need to educate primary and reproductive health care providers, regarding their role in proper HIV education, counseling, and testing.

McClelland R.S. et al. Treatment of cervicitis is associated with decreased cervical shedding of HIV-1. AIDS 15(1): 105–110 (2001).
This study measured HIV-1 RNA shedding following treatment for cervicitis in 36 out of 70 eligible HIV positive women in a sexually transmitted infection clinic in Mombasa, Kenya. HIV-1 RNA levels were checked before and after treatment with antibiotics for 16 women with gonorrhea, 7 with chlamydia, and 13 with non-specific cervicitis. Results showed 26 of the 36 women (72%) had a decrease in HIV-1 RNA after the successful treatment of their cervicitis. When broken into subgroups, the treatment did not produce a statistically significant decrease among the women with non-specific cervicitis. Median HIV-1 RNA decrease overall was from 4.05 to 3.24 log 10 copies per vaginal swab (a sixfold decrease). The treatment also reduced cervical inflammation. Effective treatment of sexually transmitted infections in HIV-positive women may help reduce their infectivity.

OFarrell, N. Genital ulcers, stigma, HIV, and STI control in sub-Saharan Africa. Sexually Transmitted Infections 78:143–146 (2002).
The author of this article examines the effect of stigma on prevention of HIV and other STIs, particularly in the context of genital ulcers. Public-health authorities have been remiss in addressing genital ulcers, probably because of both uneven epidemiological evidence (including a lack of emphasis on the importance of clinical examinations to detect ulcers) and a fear of stigmatizing those likely to have genital ulcers. The author advocates for men to recognize and accept that they are the main vectors of HIV infection and that high HIV transmission rates from core groups are fueling the epidemic. "The importance of genital ulcers should be reassessed and publicized."

Pisani, P. et al. Cancer and infection: estimates of the attributable fraction in 1990. Cancer Epidemiology, Biomarkers, and Prevention 1:387–400 (June 1997).
This article, written by researchers from the International Agency for Research on Cancer (IARC), reviews the evidence linking various cancers to infectious agents, including cervical cancer and HPV infection. The article includes data from around the world and concludes that over 90 percent of cervical cancer cases in the developing world can be directly attributed to HPV infection.

WHO. Guidelines for Sexually Transmitted Infection Surveillance. Geneva: WHO (1999). Available at: www.unaids.org/publications/documents/impact/std/JC240-SexTransmInfSurv-E.pdf.
This document was produced by the UNAIDS/WHO Working Group on Global HIV/AIDS/STI Surveillance. The five components of STI surveillance necessary for effective control programs are case reporting; prevalence assessment and monitoring; assessment of STI syndrome etiologies; antimicrobial resistance monitoring; and special studies. The document offers detailed guidelines for implementing these components, as well as guidelines for basic and advanced surveillance, the classification of HIV/AIDS epidemics, and guidelines for disseminating, communicating and utilizing STI surveillance data, and evaluating STI surveillance systems. This document is available in English and Spanish.

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Male circumcision and HIV

Also see the Special Report from the September 18, 2002, male circumcision conference.

Bailey, R. et al. The acceptability of male circumcision to reduce HIV infections in Nyanza Province, Kenya. AIDS Care 14(1):27–40 (2002).
This study was conducted with a traditionally non-circumcising population of the Luo ethnic group in western Kenya to determine the acceptability of male circumcision among this population. Focus group discussions with Luo men and women explored perceptions of male circumcision, barriers to male circumcision, and facilitators to acceptance of circumcision. The main barriers included cultural tradition and cultural identity, fear of pain from the procedure and from the healing process, complications of the procedure such as bleeding or infection, costs of the procedure, and lack of easily accessible, reliable health services. Participants identified two main facilitating factors for accepting male circumcision: increased hygiene and reduced risk of transmission of HIV and other STIs. Semi-structured interviews with clinicians revealed that clinicians lacked the appropriate information and skills to counsel clients on the risks and benefits of male circumcision and to be able to safely perform the procedure. Further research is needed to determine whether the level of acceptability for male circumcision among the Luo would be valid for other non-circumcising regions in sub-Saharan Africa.

Bailey, R. et al. Male circumcision and HIV prevention: current knowledge and future research directions. Lancet Infectious Diseases 1(4):223–231 (2001).
This article reviews the epidemiological evidence from studies reporting an association between male circumcision and reduced risk of HIV infection. The article discusses potential confounding factors—such as circumcision's protective effect against other sexually transmitted infections, the age at circumcision, religion, ethnicity, cultural practices, genital hygiene, and misclassification of circumcision status—that make interpreting the data difficult. The authors recommend conducting randomized trials to control for these potential confounders, and to assess other important issues such as the complications of the procedure and the risk of behavioral disinhibition after the procedure that may make men more likely to engage in risky sexual behavior. Additional research should address programmatic issues related to introducing the service, including the need for training, facilities, and supplies, and the associated costs. Communities and individuals should be given the strongest evidence available upon which to base their decisions.

Bonner, K. Male circumcision as an HIV control strategy: not a "natural condom." Reproductive Health Matters 9(18):143–155 (November 2001).
In this article, the author notes that recent studies have demonstrated with consideration conviction the association of a reduced risk of HIV infection with male circumcision among high-risk populations in sub-Saharan Africa. She argues that there are significant risks associated with circumcision, given that it is a surgical procedure, and that circumcision has strong cultural and religious connotations in many places, suggesting ethical and practical obstacles to applying circumcision as a public-health measure. Although it appears that circumcision may reduce the risk of infection, it is not clear that it decreases rates of HIV transmission from HIV-positive men to their partners. Until more is learned about the links between circumcision and STIs, the best recourse is to implement prevention methods of proven effectiveness, such as condom use.

Cold, C. and Young, H. To promote circumcision as a preventive measure against human immunodeficiency virus transmission is irresponsible. [letter to the editor]. Journal of Infectious Diseases 181:1864–1865 (May 2000).
This letter discusses statistical validity of the Lavreys et al. (1999) article, which suggests an association between lack of circumcision and susceptibility to HIV infection. These authors maintain that the small sample size of the earlier study prevents meaningful statistical conclusion. In addition, the authors mention the difficulty of separating ethnicity and uncircumcised status, and that ethnicity may play a role in sexual practices that may have influenced findings of Lavrey et al. This letter concludes that strategies to prevent HIV/AIDS must incorporate the reality of human behavior (in which an individual who has undergone this painful procedure may not modify his behavior), and that unsafe sex will promote HIV transmission, whether a man is circumcised or not.

Gray, R. et al. Male circumcision and HIV acquisition and transmission: Rakai, Uganda [letter]. AIDS 16(5):809–810 (March 29, 2002).
This letter provides a response to an earlier commentary on the Gray et al. (2000) article on male circumcision and HIV acquisition and transmission. Here, Gray et al. describe the complexity of drawing conclusions linking male circumcision to the reduction of risk of HIV acquisition. The only available data are from observational studies, which can lead to an overestimate of the risk reduction associated with an intervention. The letter lays out three reasons why broad promotion of male circumcision as a prevention strategy could be premature without evidence from randomized controlled trials. The first reason addresses the issue of ensuring that the introduction of circumcision services is feasible and cost-effective before re-allocating resources from other effective prevention efforts. Second, the authors raise the concern over the potential for circumcised men to feel fully protected and therefore engage in high-risk behaviors that could increase rates of HIV transmission. Third, the authors caution that in a community-wide program, men who are already HIV-positive likely will seek circumcision services; the safety of the procedure for HIV-infected men and their partners has yet to be evaluated.

Gray, R. et al. Male circumcision and HIV acquisition and transmission: cohort studies in Rakai, Uganda. AIDS 2000 14(15): 2371–2381 (2000).
In context of the Rakai STD Control for AIDS Prevention Study in southwestern Uganda, this paper presents a retrospective analysis of the effects of circumcision on HIV acquisition in a cohort of 5,507 initially HIV-negative men, representing a population with moderate potential for HIV acquisition and transmission. In 187 HIV-negative men in relationships with an HIV-positive partner, there were no seroconversions in 50 HIV-negative circumcised men, whereas there were 40 seroconversions in the 137 uncircumcised men (HIV acquisition rate of 16.7 per 100 person-years). The influence of male circumcision on HIV transmission rate was also assessed in 223 HIV-positive men partnered with HIV-negative women. The HIV transmission rate was not statistically significant except when the viral load was less than 50,000 viral copies/ml. These findings suggest that the protective effects of circumcision may be lower or negligible in certain subgroups, and that protective effects may be influenced by intensity of HIV exposure. The authors discuss the impact of cultural and behavioral factors of religious beliefs on the study results, and conclude that randomized trials are required to assess whether voluntary male circumcision is an appropriate intervention for HIV prevention.

Halperin, D. et al. Response to Ronald Gray, Male circumcision and HIV acquisition and transmission: cohort studies in Rakai, Uganda (2000, 14:2371–2381). AIDS 16(5):810–812 (March 29, 2002).
This letter advocates for stronger promotion of male circumcision as a prevention strategy for HIV transmission based on the evidence available from the Rakai, Uganda, study and observational studies supporting the association between male circumcision and reduced risk of acquiring HIV among men. The letter cites strong biological evidence of the protective effect of circumcision and preliminary data from acceptability studies that show the concern over the dis-inhibition effect of circumcision may be unfounded. While results of the first randomized trial are years away, the authors encourage moving forward with information dissemination and education about the risks and benefits of circumcision, and the integration of pilot programs for safe, affordable circumcision services into reproductive health and STI/HIV programs.

Lagarde, E. et al. Acceptability of male circumcision as a tool for preventing HIV infection in a highly infected community in South Africa. AIDS 17(1):89–95 (2003).
This article reports on a study conducted among 482 men aged 19 to 29 and 302 women aged 14 to 25, in the Westonaria district of South Africa. The study, carried out in August and September 2001, was designed to measure the prevalence and related factors of male circumcision and to consider its feasibility in preventing HIV infection. After randomly selecting the subjects and obtaining their written consent, interviewers first transported the participants to a local facility and applied a questionnaire to determine various aspects of background variables, sexual behavior, health issues, and perceptions and beliefs about male circumcision. Clinical examinations then provided an opportunity for HIV testing of participants and examination of the male foreskin. Of the male participants, 108, or 31 percent, reported being circumcised. Results of the study supported the feasibility of an HIV prevention program that would include male circumcision but stressed the need to address the belief of many participants that circumcision would protect them from HIV infection.

Lamptey, P. Reducing heterosexual transmission of HIV in poor countries. British Medical Journal 324:207–211 (2002).
This review highlights the economic, social, and health impact of HIV/AIDS in developing countries. The author provides a discussion of factors facilitating heterosexual transmission of HIV and successful prevention measures based on an extensive literature search and review, and international experience. Among the six key factors listed that promote heterosexual transmission of HIV are frequent change of sexual partners; unprotected sexual intercourse; presence of sexually transmitted infections and poor access to treatment; lack of male circumcision; social vulnerability of women and young people; economic and political instability of the community. The article concludes with a discussion of challenges for the future of preventing heterosexual HIV.

Lavreys, L. et al. Effect of circumcision on incidence of human immunodeficiency virus type 1 and other sexually transmitted diseases: a prospective cohort study of trucking company employees in Kenya. Journal of Infectious Diseases 180:330–336 (August 1999).
The goal of this study was to determine the effect of circumcision on acquisition of HIV and other STDs. A total of 746 HIV-seronegative trucking company employees in Mombasa were enrolled in a prospective cohort study between March 1993 and June 1997. During the course of follow-up, 43 men became infected with HIV, yielding an annual incidence of 3.0 percent. The annual incidences of genital ulcers and urethritis were 4.2 percent and 15.5 percent, respectively. In multivariate analysis, after controlling for demographic and behavioral factors, uncircumcised status was an independent risk factor for HIV infection (4-fold increased risk) and genital ulcer disease (2.5-fold increased risk). The association between circumcision and HIV infection was independent of genital ulcer disease, which was thought to be the causal pathway between circumcision and HIV acquisition. The authors acknowledge that attitudes toward male circumcision may be difficult to change in some settings, but they encourage researchers to conduct acceptability studies, particularly in high HIV-prevalence settings, to begin assessing feasibility of circumcision promotion.

Weiss, H. et al. Male circumcision and risk of HIV infection in sub-Saharan Africa: a systematic review and meta-analysis. AIDS 2000 14:2361–2370 (2000).
This paper systematically reviews 27 studies of male circumcision and the risk of HIV-1 infection in men in sub-Saharan Africa. Utilizing a random- effects meta-analysis of the literature, this study calculated a reduced risk in circumcised men that is approximately half that of uncircumcised men. When analyzing only the 15 studies that adjusted for potential confounding factors, they calculated greater reduction of relative risk among circumcised men, with the reduction stronger in men at high risk of HIV infection than in men in general populations. This study concludes that consideration should be given to the acceptability and feasibility of providing safe services for male circumcision as an additional HIV prevention strategy.

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Future directions: vaccines and microbicides

Beyrer, C. The HIV/AIDS vaccine research effort: an update. The Hopkins HIV Report (January 2003). Available at: www.hopkins-aids.edu/publications/report/report_toc.html.
This thorough, comprehensible article describes the current state of research for a vaccine against HIV/AIDS. The author maps out the different classes of vaccine candidates currently under investigation, including subunit vaccines (recombinant peptides that include the envelope proteins of HIV-1, gp120, or gp160), recombinant viral vectors (in which a viral vector system delivers HIV antigens to the immune system, targeting antigen-presenting cells in lymphatic tissues), and prime boost strategies (such as the ALVAC prime followed by the VaxGen gp120 B/E boost, an approach scheduled to undergo Phase III efficacy testing in Thailand in early 2003). The author also discusses DNA vaccines, and refers to the inherent problems of live attenuated HIV vaccine approaches, which "have largely been abandoned for safety reasons, and are not being actively pursued by most groups." Locating "informed, willing, and motivated volunteers" is a major challenge to HIV vaccine efficacy trials, but remains essential. Researching approaches that stave off progression to AIDS rather than preventing infection may provide intermediate results while efforts continue to develop an effective HIV vaccine.

Blower et al. Forecasting the future of HIV epidemics: the impact of antiretroviral therapies & imperfect vaccines. AIDS Reviews. 2003;5(2):113–125.
The authors of this article examine the use of mathematical models to evaluate the potential impact of combination antiretroviral therapies and imperfect vaccines on HIV epidemics. In the case of antiretroviral therapy, calculations demonstrate that an increase in risky behavior of as little as ten percent could “counterbalance the benefits of even a high level (50-90% of HIV-infected cases treated) of ART in decreasing transmission.” In the area of drug resistance, high rates of treatment with antiretrovirals could reduce the percentage of drug-sensitive infections but increase the percentage of drug-resistant infections. In this area, the authors recommend focusing public health efforts on minimizing the rate of acquiring resistance rather than on preventing the transmission of antiretroviral-resistant strains. In the case of application of an imperfect vaccine with a view to eradicating HIV, the authors suggest that a larger proportion (as much as 100 percent) of the population in an area with a severe HIV epidemic would need to be vaccinated than in an area with a moderate HIV epidemic. In the case of low-impact vaccines, an increase in risky behavior would have the effect of aggravating the epidemic.

Clements CJ, Abdool-Karim Q, Chang ML, et al. Breaking new ground--are changes in immunization services needed for the introduction of future HIV/AIDS vaccines and other new vaccines targeted at adolescents? Vaccine. 2004;22(21–22):2822–2826.
Given that young people aged 15 to 24 account for nearly half of all new HIV infections worldwide, even younger people (e.g., pre- and early adolescents) may become one of the primary target groups for future HIV vaccines. HIV vaccination may take place within services that currently offer primary care, HIV voluntary counseling and testing, management of sexually transmitted infections, family planning, and condom distribution. In the case of young people, HIV vaccination may be offered within schools and comprehensive adolescent health programs.

Emini E, Koff W. Developing an AIDS vaccine: need, uncertainty, hope. Science. 2004;304(5679):1913–1914.
In this article, the authors maintain that the best approach to controlling the spread of HIV is the development and administration of an effective vaccine. The most likely vaccine may be one that obtains specific cellular immunity by increasing the number of anti-HIV CD4+ memory and CD8+ cytotoxic T lymphocytes in an uninfected person. When the person confronts HIV infection, the memory cells will then have the ability to multiply rapidly and maintain a low viral load, with corresponding benefits for the immune system and the health of infected people.

Esparza, J. et al. Past, present and future of HIV vaccine trials in developing countries. Vaccine 20:1897–1898 (2002).
The authors of this article state the necessity for conducting vaccine research and trials in developing countries due to the large number of infections occurring in developing countries; the need to carry out Phase III efficiency trials in populations with a high incidence of HIV infection; the genetic and antigenic variability of the virus, requiring the testing of candidate vaccines in different parts of the world; and the need to evaluate how varying transmission paths and co-factors impact the protection provided by vaccines. They note that the first generation of HIV vaccines, based on monomeric bivalent BB and BE gp120, began Phase III efficacy evaluation in 1998 in the United States and in 1999 in Thailand. Results should become available in the next two to three years. The first Phase I/II trials in Africa began in 1999 in Uganda (using a subtype B canarypox-HIV recombinant candidate vaccine) and in 2001 in Kenya (using a subtype A DNA vaccine). The authors argue for conducting multiple Phase I/II trials "to assess the safety and immunogenicity of different candidate vaccines," with the goal of choosing the most promising candidates for Phase III efficacy trials; they also highlight the need to plan for the use of HIV vaccines, once they are developed. A particular focus on developing vaccines for Africa is in order.

Esparza, J. and Bhamarapravti, N. Accelerating the development and future availability of HIV-1 vaccines: why, when, where, and how? Lancet 355:2061–2066 (June 10, 2000).
This article describes the need for an HIV-1 vaccine to control the AIDS pandemic, especially in less-developed countries. To this end, there is a need to increase vaccine research and extend vaccine concepts into candidate vaccines appropriate for clinical evaluation. The first Phase III efficacy trial began in 2000. To accelerate vaccine development, it is suggested that financial mechanisms be developed as an incentive to the vaccine industry and to facilitate the availability of vaccines in less-developed countries.

Garber DA, Silvestri G, Feinberg MB. Prospects for an AIDS vaccine: three big questions, no easy answers. Lancet Infectious Diseases. 2004;4(7):397–413.
This article states that most efforts to develop an HIV vaccine are currently focused on the ability of cytotoxic T lymphocytes to render immunized people capable of controlling viral replication when they become infected with HIV, rather than granting them complete protection from HIV infection. Low viral loads would hopefully also decrease the risk of secondary transmission and mitigate the spread of HIV. The cytotoxic T lymphocyte strategy would create a pool of HIV-specific CD4+ T-helper cells that would help generate sufficient numbers of antiviral CD8+ T cells. HIV diversity complicates the development of an effective HIV vaccine with the first two phase III efficiency trials on humans yielding disappointing results. Cost and implementation are also important obstacles, particularly in low-resource environments. Additional practical difficulties include complex vaccine manufacturing processes, the need to preserve vaccines in extreme environmental conditions, and complicated immunization procedures that may be necessary to produce strong immune responses in those undergoing vaccination.

Garber D, Feinberg M. AIDS vaccine development: the long and winding road. AIDS Reviews. 2003;5:131–139.
In this article, the authors maintain that HIV is a difficult target for antibody neutralization, due in part to rapid virus evolution and the emergence of neutralization-resistant mutants. The enhancement of antiviral CD8+ T-cell responses may help control HIV infection, but HIV genetic diversity, including the capacity of HIV to evolve rapidly in vitro, constitutes an obstacle to vaccine design. HIV infection of CD4+ T-cells presents a further challenge to vaccine design. Although a large number of clinical trials of candidate HIV vaccines are underway, there are limitations in the use of non-human primate models for pre-clinical evaluation of HIV/AIDS vaccines.

Hu, D. et al. Key issues for a potential human immunodeficiency virus vaccine. Clinical Infectious Diseases 36:638–644 (March 2003).
This article discusses issues related to a partially effective vaccine for use in the United States. The authors assert that even a partially effective vaccine "could significantly reduce the severity of HIV epidemics” in countries with high incidence of HIV infection, if administered at a high level of coverage. The success and sustainability of any HIV immunization program, however, will necessitate “preparation of medical providers, the general community, and high-risk populations,” “development of a medical infrastructure that can access and follow these varied high-risk populations,” “expansion of comprehensive, ongoing prevention programs,” and “establishment of funding mechanisms for vaccination of adults in populations of nonelderly individuals.” The authors also point to the importance of developing mathematical and decision-analysis models for HIV vaccine use; social, behavioral and community assessment; and collaborative epidemiological and applied laboratory research.

Idemyor V. Human immunodeficiency virus: scientific challenges impeding candidate vaccines. HIV Clinical Trials. 2003;4(6):421–424.
The author of this article states that the key issues in developing an HIV vaccine “include identification of the protective immune responses to infection and the identification of the viral gene products against which the host products are directed.” The vaccine methodologies currently being considered include peptide-based, oligomeric envelope protein, recombinant Tat, adjuvants, and DNA. Despite the amount of effort underway to develop an effective HIV vaccine, a remaining obstacle is the inability to produce antibodies capable of neutralizing a wide spectrum of primary HIV strains.

Johnston, R. Microbicides 2002: an update. AIDS Patient Care and STDs 16(9): 419–430 (2002).
This article presents highlights of the International Microbicides 2002 Conference, held in Belgium in 2002. Effective microbicides must provide a barrier function and “contain an active anti-HIV agent that kills or permanently disables the virus.” Microbicides must also contain pharmacological agents that are toxic to viruses but not to the vaginal mucosa. The author notes the consensus that nonoxynol-9, which trials showed to be associated with a greatly enhanced risk of genital ulcers, is both not recommended and potentially harmful if used against HIV and other STIs. However, several other types of microbicide are currently under development. These include the “Invisible Condom,”™ a thermoreversible gel that assumes a liquid form at room temperature and is solid at body temperature. Sulfated polymers are another type of microbicide under development. These include naphthalene sulfonate polymer, binding/fusion/entry inhibitors, and carrageenan (the Carraguard™ brand—derived from red seaweed and generally used as a thickening agent in ice cream and soups—currently the best known and most advanced microbicide candidate). The option of using microbicides for anal sex is also important. All potential microbicides must undergo in vitro and in vivo testing before proceeding to clinical trials.

What if we had an AIDS vaccine? [editorial]. Lancet 356(9224):85 (July 8, 2000).
This editorial summarizes the current need for an AIDS vaccine, the obstacles behind meaningful behavior change as a means to control the HIV/AIDS epidemic, and the technical and financial issues faced by the International AIDS Vaccine Initiative (IAVI). The need to tailor an AIDS vaccine and immunization schedule to particular regions may further complicate AIDS vaccine development and delivery. The development of an AIDS vaccine also faces considerable challenges such as lack of political commitment, ethical oversight, need for effective regulation, local infrastructure and trained personnel.

Letvin, N. Strategies for an HIV vaccine. The Journal of Clinical Investigation 110(1):15–20 (July 2002).
This article seeks to consider the particular problems for vaccine development inherent in the biology of HIV infection. It also aims to summarize recent advances in understanding of the immune control of HIV and their implications for vaccine development. Currently, several vaccine strategies are focusing on the importance of CTLs in controlling the spread of HIV. These methods hinge on the use of plasmid DNA, live recombinant viral vectors, and combined modality or prime/boost approaches. The resulting vaccines have not produced immunity preventing HIV infection in monkeys, but they have generated immunity contributing to the containment of viral replication following infection. These strategies are now in the early testing stages on human volunteer populations. There is a growing conviction that it may be possible to produce an HIV vaccine capable of slowing disease progression, if not yet one that prevents infection.

Mwau, M. and McMichael, A. A review of vaccines for HIV prevention. The Journal of Gene Medicine 5:3–10 (2003).
This review underscores the complexity of the human immunodeficiency virus and the possibility that researchers will not be able to develop a preventive vaccine. HIV has demonstrated the ability to mutate efficiently to evade antibody attack, including the mutation of critical amino acids in peptide epitopes that effectively renders them unrecognizable by CTL. The CD8+ T cells observed in chronic HIV infection are deficient, and the CD4+ T cells lose their protective function when attacked soon after HIV infection occurs. Killer T cells are incapable of finding HIV when it retreats to lymphoid organs, the central nervous system, and infected resting CD4+ T cells. However, the likelihood is strong that researchers will develop vaccines that prevent or slow the progression to AIDS. An antibody that "binds efficiently to the virus and is present in large enough quantities before or soon after exposure" is also believed capable of protecting people against HIV infection. "[T]he challenge lies in increasing the numbers and types of candidate vaccines, bolstering the participation of major stakeholders, sourcing of adequate funding and animal models, and stimulating a healthy demand for HIV vaccines."

Stone, A. Microbicides: a new approach to preventing HIV and other sexually transmitted infections. Nature Reviews: Drug Discovery 1:977–985 (December 2002).
This article discusses microbicides as products containing anti-infective chemicals proven to block HIV and other STIs. Women could insert these products—in the form of gels, creams, foams, impregnated sponges, suppositories, or films—in the vagina before sexual intercourse. The ideal microbicide would be colorless, odorless, tasteless, and easy to use. During trials held in Nairobi, Kenya, the microbicidal candidate nonoxynol-9 "did not protect against HIV, gonorrhoea or chlamydia, and seemed to be responsible for genital ulcers in some of the women.” The problems associated with nonoxynol-9 have underscored the need to develop microbicides that do not damage the vaginal mucosa or affect the vaginal lactobacilli. Microbicide combinations are also a possibility, in the search for maximum protection, and efforts are also under way to develop microbicides for rectal use. Microbicides scheduled to enter Phase III trials include carrageenan, BufferGel, PRO 2000, and dextrin-2-sulphate.

Tramont E, Johnson M. Progress in the development of an HIV vaccine. Expert Opinions on Emerging Drugs. 2003;8(1):37–45.
The ultimate, though elusive goal of an HIV vaccine is to achieve a level of effectiveness that would sterilize the human immunodeficiency virus. Potential immune correlates that could serve as the basis for the development of a candidate HIV vaccine include systemic or mucosal neutralizing antibodies, cytotoxic T cells, and secreted anti-HIV factors such as macrophage inflammatory proteins, other chemokines secreted by T cells and non-immune cells, and defensins. Vaccine strategies under development include selected viral proteins, live vectors expressing HIV proteins, and naked DNA. An innovative approach to preventing HIV transmission would be to boost women’s immunity with the use of a vaccine-laced tampon during menstruation or to colonize the vagina with “naturally occurring, harmless organisms (e.g., lactobacillus) modified by recombinant technology to reduce HIV-specific immune responses in the female genital tract.”

Weidle, P. et al. HIV/AIDS treatment and HIV vaccines for Africa. Lancet 359(AIDS in Africa IV):2261–2267 (June 29, 2002).
The authors of this article examine the need to combine widespread antiretroviral treatment of people living with HIV/AIDS in Africa with work to develop effective preventive vaccines. People with symptomatic disease should have priority access to treatment. It is important not to use antiretroviral drugs in a disorganized manner, as this could lead to widespread drug resistance. There is a need to find ways to increase access to care and to develop simplified monitoring mechanisms for positive and negative treatment effects. Three small-scale Phase I HIV vaccine trials were conducted and Uganda and Kenya, and were instrumental in demonstrating that such trials could be carried out successfully in Africa. As vaccine development moves forward, it is necessary to plan for generalized access to any HIV vaccine that proves effective during Phase III trials, including planning for obtaining and distributing vaccines.

WHO. WHO/CONRAD Technical Consultation on Nonoxynol-9: Summary Report. Geneva: WHO (2002). Available at: www.who.int/reproductive-health/rtis/N9_meeting_report.pdf.
This report emanated from a meeting held in Geneva in 2001. The goal of the meeting was to review the evidence concerning a number of issues related to nonoxynol-9: the use of nonoxynol-9 containing products in developed and developing countries; toxicology; clinical safety data; effectiveness for pregnancy prevention; effectiveness for prevention of sexually transmitted infections; and safety of rectal use. Participants recommended that nonoxynol-9 not be used for STI- or HIV-prevention purposes; that it be considered as a contraceptive option among women at low risk of HIV infection, but not for women who have multiple daily acts of intercourse; that it not be used rectally; that N-9-lubricated condoms no longer be promoted, although it is better to use an N-9-lubricated condom than none at all. The report also identified several key areas for further research.

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