Global Response to HIV: Treatment as Prevention, or Treatment for Treatment?

Abstract

The concept of “treatment as prevention” has emerged as a means to curb the global HIV epidemic. There is, however, still ongoing debate about the evidence on when to start antiretroviral therapy in resource-poor settings. Critics have brought forward multiple arguments against a “test and treat” approach, including the potential burden of such a strategy on weak health systems and a presumed lack of scientific support for individual patient benefit of early treatment initiation. In this article, we highlight the societal and individual advantages of treatment as prevention in resource-poor settings. We argue that the available evidence renders the discussion on when to start antiretroviral therapy unnecessary and that, instead, efforts should be aimed at offering treatment as soon as possible.

Mounting scientific evidence suggests that early initiation of antiretroviral therapy (ART) reduces morbidity and mortality, and in addition can reduce incidence rates of human immunodeficiency virus (HIV). As a result, the concept of “treatment as prevention” has emerged as a means to curb overall disease burden, and ultimately control the global HIV epidemic [1–3]. These new insights should dictate global treatment guidelines and priorities for future research. Indeed, US guidelines now advise initiation of ART regardless of CD4⁺ cell count [4, 5], and World Health Organization (WHO) guidelines have recently moved to recommend ART initiation at a CD4⁺ count of 500 cells/µL, as well as regardless of CD4⁺ cell count in a number of specific settings (ie, comorbidities such as hepatitis B virus or tuberculosis, serodiscordant couples, pregnant women, and children ≤5 years of age) [6]. There is, however, still ongoing debate about the evidence on when to start treatment in resource-poor settings. Critics have warned that implementing treatment as prevention could jeopardize already precariously low funding for other HIV prevention interventions, and burden frail health systems [7]. Others have put forward various arguments against a “test and treat” approach in pregnant women, including the ethical concern of prioritizing women over men, potentially leading to community tensions [8]. Experts have proposed to perform a randomized controlled trial comparing the health benefits of early vs deferred ART in African populations [9], although such studies are already ongoing, including a cluster-randomized trial to evaluate the population-level and individual effects of immediate ART initiation in South Africa [10]. We believe that ample evidence on the favorable effects of early ART initiation is already available to the support the implementation of this strategy in sub-Saharan Africa. In this article, we highlight the societal and individual benefits of treatment as prevention in resource-poor settings and try to address the real and perceived obstacles that thwart its widespread implementation.

PROGRAMMATIC CONSIDERATIONS

Currently, not everyone with CD4⁺ cell counts <350 cells/µL has access to HIV treatment. The new WHO guidelines increase the total number of people eligible for ART from 17 million to 26 million in resource-limited settings globally [6]. If we are not able to treat all HIV-infected persons with precariously low CD4⁺ cell counts, how can we spend money on people who are not yet in the immunological danger zone? This is a compelling question, but the reasoning is flawed. Eventually, everyone living with HIV will need lifelong treatment to stay alive. The most rational approach would be to offer treatment in a way that maximizes both individual and public health benefits, that is, as early as possible. For the individual, the “extra” time spent on ART by early treatment initiation will be negligible compared with the expected total duration of ART, which is measured in up to 50 years [11]. Moreover, the International AIDS Vaccine Initiative recently found in a cohort with known time of incident HIV infection in eastern and southern Africa that the median time from infection to reaching the new WHO eligibility criterion for ART initiation at a CD4⁺ cell count ≤500 cells/µL was as brief as 6 months for men and 8 months for women [12].

Current ART programs in many sub-Saharan countries are challenged by poor health infrastructure, unreliable laboratory and pharmacy support, and lack of human resources. The workforce crisis in the African region is acute: Whereas the continent carries an estimated 24% of the global burden of disease, it has only 3% of the world's healthcare workers (Table 1) [13]. It would therefore seem impossible to scale up HIV testing efforts and put millions of extra people on treatment with the present level of funding. A recent model-based analysis of the HIV Prevention Trials Network 052 study data, however, projected the economic effects of treatment as prevention among serodiscordant couples in South Africa and India, and found early ART to be very cost effective over the long term in both countries [14]. In South Africa, a middle-income country, early ART was even cost saving over the first 5 years, as the cost of ART was more than offset by the prevention of expensive-to-treat opportunistic infections. This model did not account for the increased productivity of HIV-infected people with higher CD4 counts, which was highlighted by a recent study from Uganda [15]. Thus, comprehensive evaluation of the individual and societal impacts of immediate initiation of ART increasingly point to the fact that this strategy can be cost averting in the short term, as has been previously proposed [16].

Table 1.

Top 10 HIV/AIDS Adult Prevalence Countries and Physician Density

Country	HIV/AIDS Adult Prevalence Rate, %	People Living With HIV/AIDS, No.	Physician Densitya	Rank (Out of 188 Countries)
Swaziland	25.9	180 000	0.16	151
Botswana	24.8	320 000	0.34	130
Lesotho	23.6	290 000	0.05	172
South Africa	17.8	5 600 000	0.77	108
Zimbabwe	14.3	1 200 000	0.16	152
Zambia	13.5	980 000	0.06	169
Namibia	13.1	180 000	0.37	128
Mozambique	11.5	1 400 000	0.03	180
Malawi	11.0	920 000	0.02	185
Uganda	6.5	1 200 000	0.12	157

Source: CIA World Factbook (https://www.cia.gov/library/publications/the-world-factbook/) (as of 1 January 2012).

Abbreviation: HIV, human immunodeficiency virus.

^a The number of medical doctors, including generalist and specialist medical practitioners, per 1000 population. By contrast, the physician density of the Netherlands is 3.92 per 1000 population (rank 13).

In low-income, high-HIV-prevalence countries, however, upfront expenditures are a major barrier to implementation of early ART initiation. It is clear that for these settings, innovative mechanisms for health financing are necessary to mobilize additional resources [17]. We propose that this be performed through a mechanism such as the Innovative Financing for Immunisation program, which currently provides the largest share of the funding of the GAVI Alliance [18]. The program converts long-term donor government pledges to immediately available cash resources by issuing bonds in the capital market. This innovative way of using official development assistance creates predictable and stable funding, allowing low-income countries to plan for longer periods [17]. Obviously, with the growth of many economies in sub-Saharan Africa, recipient countries may also take a greater share in the burden. The above-mentioned cost-effectiveness study indicates that early ART initiation provides an excellent return on investment [14].

Besides innovative financing, more efficient and affordable ways of healthcare delivery will need to be further developed and implemented. One important context-specific model, which has shown promising results, is task shifting of HIV care from specialized physicians to appropriately trained healthcare workers [19, 20]. Treatment as prevention can only be achieved if more task shifting takes place, alongside the training of additional healthcare workers and peers. Fortunately, early ART initiation facilitates task shifting, because treating asymptomatic individuals simplifies the delivery of ART. Moreover, persons diagnosed with HIV will not have to wait for CD4⁺ cell count results before initiation of therapy, reducing pre-ART clinic visits and the risk of patient attrition.

The investments in health systems necessary for the early initiation of ART will be beneficial for the management of other chronic conditions, such as noncommunicable diseases, which are an increasing burden in low- and middle-income countries. Instead of worrying about whether funding for HIV treatment will diverge funds from general health services, it is crucial to realize that HIV cannot be treated in isolation. The rational approach would be to measure blood pressure and glucose along with performing an HIV test when individuals present to the clinic, a strategy which has been successfully pioneered in Uganda [21]. In fact, integrating HIV care into primary care has recently been shown to improve survival of patients on ART [22].

PREGNANT WOMEN

Routine HIV testing among pregnant women in antenatal care clinics represents a unique opportunity to implement early treatment initiation. Currently, only 30% of eligible HIV-infected pregnant women are accessing any form of treatment, which is substantially less than coverage in the general population [23]. This statistic emphasizes that, instead of discussing when to start ART, efforts should be aimed at optimizing HIV testing among pregnant women, and initiating treatment as soon as possible, with appropriate adherence support.

There are several distinct advantages of offering lifelong treatment to pregnant women instead of short-course ART for the prevention of vertical transmission with each subsequent pregnancy. First and foremost, it will protect women's health. In sub-Saharan Africa, women of childbearing age are prone to rapid CD4 decline attributed to multiple pregnancies and infectious risks. In Zimbabwe, postnatal HIV-infected women not on ART were 5 times as likely to die compared with HIV-uninfected women, even at high CD4 cell counts [24]. Furthermore, starting and stopping ART has been definitively shown to be harmful by increasing the risk-opportunistic infections and premature death [25, 26]. Also, treatment interruptions markedly increase the risk of emergent HIV drug resistance, particularly to nonnucleoside reverse transcriptase inhibitors, which represent the most commonly used first-line therapeutic option globally [27–29]. Finally, lifelong ART for women could reduce vertical HIV transmission, as it has been shown that when antiretroviral drugs are stopped after the breastfeeding period, women often present too late (ie, beyond 14 weeks’ gestation) during a subsequent pregnancy, which increases the chance of in utero HIV transmission [30]. Early and lifelong treatment of pregnant women therefore represents an efficient strategy to enhance maternal and child health and to ultimately eliminate pediatric HIV.

Although men will also benefit from early ART initiation, they tend to be diagnosed at a later stage than women [31], but this is not a reason to withhold treatment from women. In fact, witnessing the benefits of early ART at home may serve as a powerful stimulus for men to access ART themselves.

TREATMENT FOR TREATMENT

There can be no doubt that starting antiretroviral drugs before the immune system is compromised (ie, when the CD4⁺ count is still >500 cells/µL), improves individual health outcomes. When treatment is started early enough, life expectancy is similar to that of non-HIV-infected individuals [32, 33]. A recent analysis by the COHERE (Collaboration of Observational HIV Epidemiological Research Europe) collaboration, comprising 33 cohorts and >200 000 individuals from Europe, indicates that the incidence of AIDS-defining illnesses is higher in individuals with a CD4⁺ cell count of 500–750 cells/µL compared with higher CD4⁺ cell numbers [34]. Early treatment for HIV also reduces tuberculosis incidence [3], which is of great importance in resource-poor settings. It also prevents the immune reconstitution syndrome; a major cause of treatment-related morbidity and mortality if treatment is started late. Finally, recent studies have indicated that treatment during primary or acute HIV infection can limit viral reservoir formation and may lead to a “functional cure” in some individuals [35–37].

Given the enormous benefits to the individual, the term “treatment as prevention” may be misunderstood, as it may be interpreted as placing the emphasis on the prevention of HIV transmission, in the absence of individual benefit, as if the societal benefits were the overriding reason to treat people early in their HIV infection. Instead, the primary aim of initiating ART is to treat the individual—in other words: treatment for treatment. Thus, treatment as prevention should be understood as the early initiation of ART to prevent disease progression, opportunistic infections, and premature death. Secondarily, it also prevents HIV transmission and reduces HIV incidence.

Of course, early ART initiation should not and cannot be achieved by forcing every person living with HIV to start treatment. If people are fully informed about the individual health benefits of ART as well as the protection offered by ART to their partners and their children, many may choose to be tested and to start ART immediately. Obviously, one of the main challenges of expanding access to treatment is maintaining adherence and retention in care, but experience with asymptomatic people on ART suggests that with the proper support, HIV-infected individuals without symptoms are able to adhere to treatment [38]. Once-daily single-tablet regimens favor adherence [39], and, in addition, simplified regimens also lower total healthcare costs [40]. Encouragingly, data from a Ugandan study have shown high retention rates in patients entering care with high CD4⁺ cell counts, under routine program conditions [41].

In summary, we want to underscore the importance of translating the scientific evidence of the benefits of early treatment initiation into worldwide policy. An AIDS-free future is possible, and we should not dwell on the hypothetically negative aspects of treatment as prevention. Instead, the focus should now shift to addressing the challenges of implementing early treatment initiation, most importantly, the major financial investments that will have to be made in low-income nations. While strengthening HIV treatment programs and minimizing patient attrition, health services should be integrated with strategies to prevent and control other chronic, noncommunicable diseases.