With declines in chancroid and syphilis globally, herpes simplex virus-2 (HSV-2) is the leading cause of genital ulcer disease (GUD). Estimates indicate that there are more than 500 million HSV-2 infected people worldwide.1 The prevalence of HSV-2 is notably high in sub-Saharan Africa with age-adjusted prevalence in women ranging from 30% to 80%.2 Congenital HSV-2 infection has high morbidity and mortality.3 Interest in the prevention and treatment of HSV-22 is stimulated by epidemiologic data that HSV-2 infection increases the risk of HIV acquisition by 2 to 3 fold.4–10 Evidence that 50% to 90% of HIV-infected individuals have concomitant HSV-2 infection suggests that HSV-2 contributes significantly to the burden of disease in HIV-infected individuals.11 Acyclovir is effective for episodic treatment of symptomatic genital herpes and suppressive therapy to reduce the frequency of HSV-2 reactivation.12,13 Even though placebo-controlled randomized clinical trials of acyclovir suppressive therapy did not demonstrate reductions in HIV acquisition or transmission,14–17 there continues to be a clinical and public health imperative to improve the diagnosis and treatment of genital herpes. In response to data on the increasing proportion of GUD because of HSV-2 globally, the World Health Organization's (WHO) 2003 sexually transmitted infection (STI) treatment guidelines formally recommended acyclovir as first-line syndromic treatment of GUD in countries with high HSV-2 prevalence (≥30%).18
In surveys conducted between 2004 and 2006, acyclovir was reported to be poorly available in public health facilities in several African countries.19 These survey findings suggested that the 2003 WHO STI guidelines recommending the use of acyclovir for syndromic treatment of GUD had not been implemented in many low-income countries. The identification of programmatic and policy issues that determine the procurement, distribution, and use of acyclovir is essential to facilitate implementation of these guidelines in sub-Saharan Africa where prevalence of HSV-2 and HIV is high. To provide such data, we surveyed procurement, distribution, and access to acyclovir in the public and private sectors of 8 countries in sub-Saharan Africa with high HSV-2 prevalence. Specifically, we assessed the extent of implementation of the 2003 WHO STI treatment guidelines about acyclovir and syndromic GUD management in country-specific essential medicines lists (EMLs) and national STI guidelines; the procurement and financing methods used by the Ministries of Health (MoHs) for the purchase of STI drugs, including acyclovir; and the cost and access to acyclovir at selected public and private pharmacies.
MATERIALS AND METHODS
Structured face-to-face interviews were conducted with MoH officials responsible for development of STI treatment guidelines and for the procurement and distribution of STI drugs for public health facilities. We also interviewed pharmacists and other pharmacy workers and reviewed records from public and private health facilities. Interviews were conducted in 2007 in Botswana, Kenya, Malawi, South Africa, Tanzania, Uganda, Zambia, and Zimbabwe. These countries were selected based on their high HSV-2 prevalence and their participation in randomized clinical trials of episodic or suppressive HSV-2 treatment with acyclovir for HIV prevention.2,15,20
A 26-item standardized questionnaire with questions regarding policies for treatment of GUD with acyclovir, as well as acyclovir procurement systems, acquisition costs, and distribution was administered to MoH officials by trained interviewers and coauthors (C.C., P.N.). Supporting documentation about STI guidelines, procurement systems, and costs of acyclovir was obtained to corroborate the information obtained in the interview. We also administered to pharmacists and other pharmacy workers in public and private health facilities a 27-item questionnaire on the cost, dispensing, and possible stock-outs of acyclovir. Pharmacists and pharmacy workers were selected from the capital city and at least one other city or town in each country studied.
Acyclovir price data were collected in local currencies and converted to US dollars using the 2007 exchange rate.21 The price data were used to make between-country comparisons of the cost of acyclovir within the public and private sectors. To enable comparisons of acyclovir in the public sector, we calculated a median price ratio, defined as the acquisition price for an acyclovir 200 mg tablet (the recommended acyclovir dosage strength listed in the 2007 WHO model list of essential medicines22) divided by the median international reference price (IRP) from the Management Sciences for Health's (MSH) 2007 International Drug Price Indicator guide.23–25 We calculated the acquisition price for the acyclovir dosage commonly used for episodic treatment of GUD (400 mg acyclovir 3 times daily for 7 days) and determined price comparisons by funding source. For the private sector, a median price ratio was determined by dividing the median retail cost of acyclovir 200 mg tablet by the median IRP. At least 4 prices were used to calculate the median price ratio for the private sector whereas only 1 acquisition price was used for the public sector.23
The surveys were conducted under a Certificate of Exemption issued by the University of Washington Institutional Review Board and respondents provided verbal consent to participate.
A total of 100 interviews were requested and all persons agreed to participate. Twenty-nine interviews were conducted with MoH officials and national STI program managers and 71 with pharmacists and other pharmacy workers based in public and private health facilities.
GUD Treatment Policy and Acyclovir Procurement Processes
Of the 8 countries, 4 (Botswana, Malawi, Uganda, and Zambia) adopted acyclovir as first-line syndromic GUD treatment in both their EML and STI guidelines (Table 1). In Tanzania, acyclovir was indicated for syndromic use in GUD in the national STI guidelines but not in their EML. The manner in which acyclovir was included in the EML for the indication of treatment of GUD influenced whether acyclovir was procured in the public sector in these 8 countries. In countries where acyclovir was indicated as first-line syndromic treatment for GUD in the EML (Botswana, Uganda, Malawi), acyclovir was routinely purchased for public health facilities and reported to be regularly available. An exception was Zambia where acyclovir was found to be out of stock at the central medical store (CMS) for more than 60 days.26 In Kenya, Tanzania, and Zimbabwe where the EML listed acyclovir as second-line treatment for GUD or for immunosuppressed patients or only for use in herpes zoster, acyclovir was reported to be frequently out of stock. South Africa was the only country where acyclovir was regularly available at the CMS, even though it was recommended in the EML as second-line treatment for GUD.
Acyclovir was procured centrally for the public sector in each country by the MoH or the CMS facility. The 200 mg tablet was the most commonly procured dosage strength. Zimbabwe was the only country where acyclovir was not purchased in the public sector. MoH officials interviewed in Zimbabwe attributed the lack of acyclovir procurement to inadequate financial resources. Acyclovir stock-outs at the CMS were reported in Kenya and Zambia, although tenders for acquisition of acyclovir were pending at the time of the survey. Countries that purchased acyclovir for the public sector used a competitive bidding process involving local, national, and international drug manufacturers and suppliers. For countries that purchased acyclovir 200 mg tablets in the public sector (Botswana, Kenya, South Africa, Tanzania, Malawi, Zambia), the acquisition price per tablet was comparable to the median IRP, and median price ratios ranged from 0.74 to 1.95.
To purchase acyclovir, countries utilized public funds and/or donor programs including the President's Emergency Plan for AIDS Relief (PEPFAR) and Global Fund to Fight AIDS, Tuberculosis, and Malaria. For countries that used public funds to purchase acyclovir, the acquisition prices for episodic treatment ranged from USD 1.44 to 3.36 for a 7-day course of episodic treatment. In comparison, countries that used donor sources to purchase acyclovir paid USD 1.05 to 1.26 per course of episodic treatment.
Acyclovir Distribution and Access in the Public Sector
We visited a total of 28 public health facilities to assess acyclovir availability. Botswana, Malawi, and South Africa were the only countries in which acyclovir was reportedly available in all public health facilities visited (data not shown). Acyclovir distribution to public health facilities was primarily demand-based, in that facilities determined the selection and volume of drugs they received from the CMS (Table 2). Kenya was the only country that used a supply based system, whereby decisions on the selection and volume of acyclovir to be distributed were decided centrally at the MoH. In 3 countries (South Africa, Tanzania, and Uganda), public health facilities were charged for receipt of acyclovir from the CMS at the acquisition price plus a 5 to 10 percent mark-up fee. Drug charges for acyclovir were reportedly waived for patients who visited public health facilities.
Pharmacists and other pharmacy workers in public health facilities identified constraints that limited access to acyclovir. For example, in Uganda, limited drug budgets available to health facilities coupled with a relatively high price of acyclovir at the CMS resulted in reports of few drug requisitions for acyclovir. In Zambia, public sector pharmacists reported that stockpiling of acyclovir was common resulting in disproportionately high amounts of acyclovir inventory in certain health facilities and inadequate amounts in other facilities. In Tanzania and South Africa respondents reported that a special order system instituted by the MoH that required a detailed summary of the patients prescribed acyclovir to be completed by a medical doctor and submitted to the CMS had resulted in few acyclovir requisitions from health facilities. Pharmacists and other pharmacy workers reported that this special order system for acyclovir resulted in long lead times between acyclovir ordering and delivery leading to acyclovir stock-outs at health facilities. Pharmacists and other pharmacy workers in Kenyan health facilities explained that acyclovir quantities received from CMS were inadequate to meet demand, resulting in stock-outs.
Cost and Access to Acyclovir in the Private Sector
Acyclovir was available in the 43 private health facilities of the 8 countries assessed (data not shown). The median retail cost of acyclovir was substantially higher than the median IRP, and median price ratios ranged from 5.85 to 9.76 (Fig. 1). Private sector pharmacists and other pharmacy workers interviewed in all 8 countries reported that the retail cost of acyclovir in the private sector depended on the brand name and the country of manufacture. For example, in Zambia, European-manufactured acyclovir generics cost up to 30 times the price of African or Indian-manufactured generics. In addition to brand name and country of manufacture, pharmacy respondents in the private sectors in Botswana and South Africa attributed the high cost of acyclovir to the high insurance coverage of their populations, for whom the price of acyclovir was reported not to be a significant concern.
This survey of 8 sub-Saharan African countries with high HSV-2 prevalence examined the extent to which countries adopted and implemented the 2003 WHO STI guidelines with acyclovir in the syndromic treatment of GUD, and assessed barriers in acyclovir procurement and access from the perspectives of MoH and pharmacists. Our findings showed that public sectors in all 8 countries faced challenges that curtailed procurement and access to acyclovir in private and public health facilities.
Acyclovir procured in the public sector through international donor organizations was less expensive than acyclovir procured through MoH resources. However, only 3 countries surveyed (Botswana, Kenya, and Malawi) reported that donor resources from organizations, such as Global Fund to Fight AIDS, Tuberculosis, and Malaria and PEPFAR, were used to purchase acyclovir for public health facilities. Sustainability of funding for acyclovir by the MoH, and when necessary, from donor sources is important, such as the Supply Chain Management System through PEPFAR, which negotiates lower costs of essential drugs through pooled procurement and long-term contracts.27 Nevertheless, the use of donor resources to purchase acyclovir should be perceived to be short to medium-term solutions as countries transition toward more long-term, sustainable programs.
The retail cost of acyclovir in the private sector was considerably higher than the median IRP. The higher cost of acyclovir in the private sector could curtail access by patients needing treatment for GUD. Our survey findings indicate that public sector purchasing in low-income countries is key to leveraging access to acyclovir, given the ability of Ministries of Health in surveyed countries (except Zimbabwe) to purchase acyclovir at low prices and provide it free of charge to patients. In addition, poor availability of acyclovir in public health facilities provides an incentive to private health facilities to increase the retail cost of acyclovir and maximize profits. Still, the private sector serves an important role in the provision of STI care given that some of our study countries experienced acyclovir stock-outs in the public sectors. Countries should therefore work toward forging public-private partnerships to ensure the provision of accessible and affordable STI care.
We compared our survey findings to surveys on drug pricing and accessibility based on methods developed by WHO and Health Action International (HAI), which included data on acyclovir for 5 sub-Saharan African countries (Ethiopia, Kenya, South Africa, Uganda, and Tanzania), conducted in 2004.19 The WHO/HAI survey reported that the retail cost of acyclovir in the private sector was 1.20 to 26 times the median IRP. Whereas our surveys found that the retail cost of acyclovir was 5.85 to 9.76 times the median IRP, this was consistent with the WHO/HAI findings of high retail costs of acyclovir in the private sector. Compared to the WHO/HAI surveys, our survey provided more current information on acyclovir in sub-Saharan African countries and included more countries from that region.
Our survey was limited by the small sample size of survey respondents and possible reporting and sampling bias. We attempted to minimize the potential for reporting bias by requesting and reviewing documentation from respondents to verify the information given. Our survey collected novel information about how each study country's STI treatment policies influenced procurement, distribution, and access to acyclovir.
Acyclovir is efficacious in shortening the duration of genital ulcers because of HSV-2, when started early after ulcer onset. Given that HSV-2 is the major cause of GUD globally and HSV-2 infection is associated with a higher risk of HIV acquisition and transmission, improvements in diagnosis and management of GUD, the majority of which is caused by HSV-2, are needed. Acyclovir suppression is effective in reducing the incidence of genital ulcers in HIV-uninfected, HSV-2 infected persons, as demonstrated in a large multisite, international randomized, placebo-controlled trial of HSV-2 suppression, although there was no reduction in HIV-1 acquisition.15 In a recent randomized clinical trial, which randomized 3408 HIV-infected persons dually infected with HSV-2 to acyclovir suppressive therapy (400 mg twice daily) or matching placebo for up to 24 months, acyclovir suppression was associated with a statistically significant reduction in average plasma HIV-1 levels and incidence of genital ulcers, and modestly delayed HIV-1 disease progression, but did not lower the rate of HIV-1 transmission to their HIV-uninfected partners.14,15 The reduction in incidence of genital ulcers and delayed HIV-1 disease progression on acyclovir suppression indicates that acyclovir could potentially offer clinical benefits to HSV-2/HIV dually infected persons.14–17,28
Revisions in the WHO STI guidelines will be issued in 2010 and will include acyclovir as first-line therapy for episodic treatment of GUD globally (WHO guidelines for the Management of Sexually Transmitted Infections 2010, in print). Implementation of the revised WHO STI guidelines will require increased access to acyclovir in public sectors especially in low-income countries. Because our surveys were conducted in the capital city and at least one other city or town in each of the 8 African countries which participated in the survey, our results may have overestimated the true status of acyclovir access, which is likely greater in capital and large cities, and therefore presented the best-case scenario of acyclovir accessibility in these particular countries. Our findings therefore underscore the need for providing assistance to low- and middle-income countries to strengthen the public sector drug procurement and supply chains for acyclovir to adopt the WHO guidelines for treatment of GUD.
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