Provision and Access
Antiretroviral therapy has been successfully administered in a range of situations with adherence, retention, and clinical outcomes similar to those achieved in resource-rich countries. Increasing provision and access, grounded in human rights based approaches, across all populations is critical to continuing that success.
"I cook scones for my children and do not get tired. I do chores, pounding. When the sun rises... I go to the garden or farm. People say, 'You have tilled that garden on your own?'" --Woman on antiretroviral treatment, Malawi (Mkandawire-Valhmu and Stevens, 2010: 690)
Treatment Must Be Equitably Available to All in Medical Need
At the end of 2013, there were 12.9 million people receiving ART globally and the percentage of people living with HIV who are not receiving ART has been reduced from 90% in 2006 to 63% in 2013 (UNAIDS, 2014a). However, further efforts are needed to ensure that treatment is equitably available to all who can benefit from ART. There are substantial treatment gaps within regions and among groups. In 2013, 37% of adults living with HIV worldwide received ART, but only 24% of children living with HIV did (UNAIDS, 2014b).
Treatment access is based on WHOs 2013 guidelines which call for a seamless continuum of care between HIV testing and counseling, linkage to care, enrollment in care, retention in care, preparing for ART plus ART initiation, with retention and adherence, and monitoring response and toxicity (WHO, 2013: 56-57).
Increased Access Must Also Include Respect for Human Rights
Expanding access to ART along with considerations of equity and human rights is urgently needed (ITPC, 2014). A recent review of data from over 50 countries found that one in eight people living with HIV is denied health care (UNAIDS, 2015). WHOs 2013 guidelines also note "human rights and ethical principles should guidenational treatment policies to ensure that they are equitable and meet the specific needs of all beneficiaries" (WHO, 2013: 202). Requiring people living with HIV to disclose their serostatus to sexual partners and/or community members in order to receive treatment, care or support is a human rights violation. Similarly, coercing women to accept contraception in order to access treatment violates women's rights to make their own fertility choices. [See Meeting the Sexual and Reproductive Health Needs of Women Living With HIV] While "treatment buddies" can be supportive, requiring a treatment buddy or medical companion to access ARV therapy may place undue burdens on women and their children: a study of 1,453 patients in Uganda (71% female) on the impact of requiring people to disclose their HIV status and have a "treatment buddy" or "medical companion" to access ARV therapy found that of the women, 41% chose a child as their medical companion versus 14% of the men. Women feared disclosing their serostatus to their husbands: only 31% of married women chose their husband as their medical companion, compared with 66% of married men who chose their wife (Foster et al., 2010b). In addition, individuals with limited networks may delay enrolling in or may drop out of care when treatment support "buddies" are required (Lahuerta et al., 2013). [See also Adherence and Support] Furthermore, in settings where the epidemic is concentrated among marginalized and stigmatized populations, such as sex workers, people who inject drugs and MSM, treatment access is also low (Hirnschall et al., 2013: para 2). [See Prevention for Key Affected Populations] Treatment programming could benefit from a conceptual framework similar to that developed for family planning, to ensure that public health programs that aim to increase treatment access and adherence "respect, protect and fulfill human rights in the way they are designed, implemented and evaluated" (Hardee et al., 2013: v).
Women and Men's Access to Treatment Differs
Men will only come to us when they are bedridden and brought to us in a wheelbarrow." --Nurse for HIV-positive men on treatment, Zimbabwe (Skovdal et al., 2011b)To date, more women than men have accessed treatment. The majority of women benefit from health system access through dedicated reproductive and child health clinics (Braitstein et al., 2008b) but it is unclear whether the majority of women accessing ART are doing so only as part of safe motherhood and prevention of vertical transmission. Global attention has often focused on prevention of vertical transmission (UNAIDS, 2011b), putting men simply in the role of supporting their HIV-positive female partners to access services, rather than caring for their own needs. Men tend to initiate treatment later, are more likely to be lost to follow up, and have higher mortality rates (Siu et al., 2012).
The Institute of Medicine notes that for PEPFAR data, each year around two-thirds of those who enroll in ART are women; the proportion has remained steady over time (IOM, 2013). Patient data from 307,110 adults from Kenya, Mozambique, Rwanda and Tanzania between 2006 and 2011 found that risk of late enrollment (CD4 counts under 350) was significantly higher for men and nonpregnant women as compared to pregnant women (Hoffman et al., 2014).
A global review based on 36 studies in resource-rich and resource-limited settings found that being a heterosexual male was a consistent risk factor for presenting with low CD4 counts, resulting in less favorable outcomes for men once enrolled in treatment (Mukolo et al., 2013). An analysis of 23 cohort studies from Africa, including 216,008 participants found that only 35% of those accessing ART were men, despite an HIV prevalence of 40%, representing "a significant underrepresentation of men in ART programs" (Druyts et al., 2013: 419). In addition, the risk of death for men was 1.37 higher than for women. However, men are seldom targeted for treatment as they are not often classified as vulnerable or marginalized (Kanters et al., 2013). While this inequitable access for men to ART may be due, in part, to a focus on maternal health, equitable access to ART for men "should be conducted without threatening HIVtreatment for women" (Druyts et al., 2013: 424).
Gender Norms Affect Treatment Access for Women and Men
Gender norms affect treatment access. A study of gender differentials in uptake to ART in Zambia found that men were more likely to refuse ART even though men's self-rated health was lower than women's, with norms of masculinity presenting the biggest barrier for male uptake of ART (Gari et al., 2014). Focus group discussions with men in Uganda found that men found it difficult to seek treatment, which contradicted their assumed masculine autonomy and superiority (Siu et al., 2013). A study of programmatic data on 334,557 adults enrolling in HIV care at 132 facilities in Kenya, Mozambique, Rwanda and Tanzania found that men were more than 1.6 times more likely to initiate ART with advanced HIV disease (CD4 count under 100) compared with women and that "this disparity seems to be widening with time" (Lahuerta et al., 2014: 435). A recent study found that men used their economic and decision-making power to informally access ART in order not to be seen at clinics, which are seen as a woman's space. Out of shame, men suffered silently and attempted to cope by stealing their wives' ARVs. The practice of men stealing ARVs from their wives endangered both partners and jeopardized women's adherence (Nyamhanga et al., 2013).
HIV is seen as a threat not just to a man's health, but to his masculinity, requiring him to seek care, challenging his notions of fearlessness, and fueling fears of humiliation and that his wife will desert him. (Nyamhanga et al., 2013)Gender norms may also be critical for the higher uptake of ARVs by women, as explained by one Vietnamese woman living with HIV: "Women have no choice but to take the drugs. Meanwhile, men are the ones who consider whether or not to take the drugs because they don't need to think of anything else except themselves" (Nguyen et al., 2012: 343). Greater attention needs to be paid to ensuring that men living with HIV know their serostatus, have equitable access to treatment, are virally suppressed and have access to condoms.
Sex Differences May Also Play a Role in Clinical Outcomes and Must Be Further Explored
Access to treatment by sex has been disaggregated in a number of studies. However, few studies have analyzed sex differences. "Although data are limited, there is also evidence that women may metabolize and respond to specific medications, including ARV drugs, differently than men" (Gandhi et al., 2004, Floridia et al., 2008, Ofotokun et al., 2007 cited in DHHS, 2011: 104). Studies to date have not shown differences in virologic efficacy of ART by sex (Collazos et al., 2007; Fardet et al., 2006; Currier et al., 2010 cited in DHHS, 2011), although "this conclusion is drawn from a limited evidence base" (d'Arminio Monforte et al., 2013: 30). ARVs are administered at fixed dosages that do not take into account the different body weight, etc. of each sex (d'Arminio Monforte et al., 2013). A study in Tanzania in which 70% of the 234 patients were women found that after one year of standard ART, a higher proportion of females had an undetectable viral load but with a lower CD4 cell increase than men. Women started treatment at a less advanced disease stage but lost their immunological advantage over men despite a better virological treatment response. In addition, men were better informed about the use of ART (Mosha et al., 2013). Other studies have found that men are disadvantaged in ART due to differences in body weight compared to dose (Tayler-Smith et al., 2010 cited in IOM, 2013).
A number of studies have suggested that gender or sex may influence the frequency, presentation, and severity of selected ARV-related adverse events (Clark et al., 2005 cited in DHHS, 2011; Hawkins et al., 2011 cited in Johannessen, 2011). One study found differences in virologic failure by sex, with women having an advantage over men (Firnhaber et al., 2012b). Another study also found that women were more likely to have viral suppression and better ART outcomes (Kipp et al., 2010) and another study found that women were in better clinical condition than men (Nunes et al., 2010). In some studies, however, women experience more adverse drug reactions than men (Hasan et al., 2011).
The research community recognizes the need to better understand the potential role of sex differences in HIV disease progression and treatment response (Heidari et al., 2010), with women under-represented in clinical trials (d'Arminio Monteforte et al., 2010). A review of forty randomized controlled trials for 18 new drug applications for antiretroviral therapy submitted to the US Food Drug Administration (FDA) between 2000 and 2008 found that only 20% of trial participants were women (Soon et al., 2012). Even when women are included, sex-specific analysis of the data is rarely undertaken (Anderson, 2012). No studies have addressed the possible interactions between ART and hormones in both men and women, including pre, peri or post-menopause (d'Arminio Monforte et al., 2013).
Pregnancy represents an additional sex-related factor in treatment. In a study of 4,531 women from numerous treatment sites in Sub-Saharan Africa, one-third experienced a pregnancy within four years of ART initiation (Myer et al., 2010). Yet few treatment programs are designed with the likelihood of pregnancy in mind (Myer et al., 2010). Most of the worlds women living with HIV are of reproductive age and will need either contraception, discussions on how best to safely become pregnant and/or have a safe motherhood and reduce the risk of vertical transmission. [See Meeting the Sexual and Reproductive Health Needs of Women Living With HIVand Safe Motherhood and Prevention of Vertical Transmission ]
Inequitable Treatment Access Affects Both Young and Old
Some studies have found that equity in access differs by age group with inadequate treatment access for adolescent women. Key affected populations, such as sex workers and those who use drugs, may face many barriers in accessing treatment as well (Ford et al., 2013b).
In 2013, there were 4.2 million people living with HIV over age 50 (UNAIDS, 2014a), and every year, almost 120,000 people in this age group acquire HIV (Nakagawa et al., 2013; Mahy, 2014). Modeling estimates that the numbers of people living with HIV over age 50 will rise to 9.1 million in 2040 in Sub-Saharan Africa (Hontelez et al., 2012). Older people living with HIV are more likely to have other chronic noncommunicable diseases, such as diabetes, cancer, and hypertension (Rabkin et al., 2012; Newman et al., 2012). Combining ART with other medications needed to treat the co-morbidities that come with aging can be challenging, with guidelines needed for this growing population (Cardoso et al., 2013). For women, menopause may increase the risk of HIV transmission and acquisition due to the thinning of the vaginal wall, with increased lesions and tears (UNAIDS, 2013). Yet little research has been conducted on the sexual behaviors of people over age 50 (UNAIDS, 2013) and most surveys, such as DHS, do not include data for those over age 50 (Bendavid et al., 2012b).
The Cost of Treatment and Service Delivery Varies Widely and Can Affect Access
Cost is another factor in treatment access. Treatment provided at no cost can substantially increase both women and men's access to ART (Musoko et al., 2011). For women especially, who may have additional barriers in accessing resources for transportation fees, childcare and more, providing treatment at no cost may substantially increase women's access.
Treatment costs vary widely between sites but per-patient costs drop rapidly as care is scaled up. Calculated costs include medication and other costs associated with providing treatment and follow-up. Across 43 PEPFAR-supported ART clinics in Botswana, Ethiopia, Nigeria, Uganda, and Vietnam, costs for providing treatment and care for a newly initiated adult on ARVs ranged from US$61 at one site to US$3,301 at another (Menzies et al., 2011). Even within the same country Kenya studies found a wide range of costs per patient per year, ranging from US$77 in one site to US$1,160 in another site (Harding et al., 2010).
The use of generic drugs can result in substantial cost savings. Annual surveys from 2005 to 2008 of ARVs purchased in 16 countries by PEPFAR implementing and procurement partners found that availability of generic ARVs was associated with increased ARV procurement and cost savings of more than US$323 million over the four year period, with generics accounting for almost 90% of the 22 million ARV packs purchased with PEPFAR funds in 2008 (Holmes et al., 2010b). South Africas scale up of treatment resulted in a 53% reduction in the cost of ART, with projected two-year savings of $640 million (UNAIDS Treatment, 2015 cited in Dilmitis, 2014).
The Optimal Timing of Initiating ART Is As Soon As Someone Is Diagnosed with HIV and Chooses to Start Treatment
"Despite potential individual and public health benefits for women living with HIV, the decision to begin treatment for HIV is a deeply personal decision that reflects a variety of private, contextual and structural factors" (ICW, 2015). In May, 2015 the U.S. National Institutes for Health (NIH) announced that the Strategic Timing of Antiretroviral Treatment (START) trial was releasing results early. With more than 4,000 individuals from more than 23 countries, the randomized clinical trial found that the risk of AIDS, other serious illnesses, or death was reduced by 53% among those who started ART immediately, compared to those who were randomized to only start ART after their CD4 count dropped to 350. The benefits of early treatment were similar for the 2,350 participants from low- and middle-income countries and the 2,155 participants from high-income countries (NIH, 2015). Given these trial results, some have argued that it is duty of all states to provide early access to treatment (Kavanagh et al., 2015). While there are clear individual and public health benefits to early treatment, efforts to promote immediate treatment access must not lose the individual within the larger public health effort and must also take into consideration the issue of autonomy that women living with HIV have consistently raised with respect to healthcare decision-making, including whether and when to start treatment. Rights to bodily integrity and privacy require that people living with HIV control their medical decisions and be provided choice in accessing treatment, rather than becoming targets of human rights violations to ensure they are adherent to ART (Kavanagh et al., 2015). People must be given the right to decline ART until they are ready.
Up until the announcement of the START results, the optimal time to initiate ART had been a subject of considerable debate (Cohen et al., 2011a: 2). Current 2013 WHO treatment guidelines recommend ART for adults with CD4 counts in the 350 to 500 cells/l range, with priority given to individuals with severe disease or CD4 counts under 350 (WHO, 2013), with revised guidelines expected in 2015. In the United States, ART is recommended as soon as a person tests HIV-positive, regardless of viral load or CD4 count (Panel on Antiretroviral Guidelines for Adults and Adolescents, 2013). In Europe, ART is not unconditionally recommended for individuals in the 350 to 500 CD4 count range (Williams et al., 2012 cited in Phillips et al., 2014).
"We now have clear-cut proof that it is of significantly greater health benefit to an HIV-infected person to start antiretroviral therapy sooner rather than laterMoreover, early therapy conveys a double benefit, not only improving the health of individuals but at the same time, by lowering their viral load, reducing the risk they will transmit HIV to others. These findings have global implications for the treatment of HIV." -- Dr. Anthony Fauci, Press release announcing START clinical trial results (NIH, 2015)While the START results demonstrate the optimal time to initiate ART, resources to ensure immediate treatment may not be available and current WHO guidelines remain in effect. Clinicians may still have to "balance the risks of delaying antiretroviral treatment against the possible harms associated with premature exposure to HAART, including side-effects, pill burden, cost and potential for avoidable antiretroviral resistance" (Nolan and Wood, 2014: 258).
Concerns have been raised about potential adverse effects, emergence of drug resistance, difficulties in access to second- or third-line ART, and exhausting treatment options if ARVs are initiated early (Socias et al., 2013). WHO guidance (WHO, 2013) provided on initiation is by CD4 count rather than by viral load. WHO notes that viral load monitoring, rather than CD4 counts, is the preferred approach for monitoring once a patient is on ART as this is a better indicator of treatment failure and helps determine if there is a need to switch to a second-line drug (WHO, 2014c; Bonner et al., 2013).
However, a lack of access to viral load monitoring in resource-limited settings may prejudice those who start antiretroviral therapy while asymptomatic and at higher CD4 counts (Gallant et al., 2013). WHO recommends that CD4 counts be used when viral load is unavailable. For countries which cannot reliably implement a deferral strategy for those who test HIV-positive yet have CD4 counts above 500, it "seems prudent to initiate ART almost as soon as a person is first identified by the care services, to decrease the risks of late re-presentation with advanced HIV symptoms" (Phillips et al., 2014: 940). For countries with limited ART coverage, a priority should be to develop "a deferral strategy though regular CD4+ cell count monitoring in order to allow prioritization of those in most urgent need" (Phillips et al., 2014: 940).
A lack of lab facilities to measure CD4 counts and viral load monitoring is a major barrier and WHO guidelines must be adapted to country contexts. "Our ongoing scientific and moral challenge will be to continue to narrow the gulf between north and south and to ensure that we do not accept the establishment of two standards of care: one for richer countries and the other for the poorer" (Granich et al., 2010: para 11). At the same time, "We must not lose sight of the glaring disparities among nations that stand as obstacles to the ethical implementation of early ART" (Gallant et al., 2013: 886).
All guidelines agree that patient readiness is key in deciding when to initiate treatment (NIDA and IAS, 2010). Interviews with people living with HIV in Zambia found that they only sought treatment when symptomatic, which may lead to delays and may present challenges for early initiation of treatment with CD4 counts up to 500 where patients are often asymptomatic (Musheke et al., 2013a).
National governments face dilemmas in how best to increase the numbers of those accessing treatment, maintain quality of care, avert loss to follow up and drug resistance while changing national guidelines to WHO's 2013 guidance to increase those who can qualify for treatment. Loss to follow up remains a critical problem: a study from South Africa found that rates of viremia were higher among those lost to follow up than for those who remained on care (Stinson et al., 2014), meaning that those who were lost to follow up were more likely to transmit HIV and to suffer mortality and morbidity. Interventions are needed to "overcome the main health system barriers such as an efficient appointment [and] patient monitoring systems and providing after-hours and weekend clinics" (Govindasamy et al., 2014b: 2).
Universal Access to Treatment Can Be Achieved
Progress is being made with treatment access: in some settings, patients who were initiated into treatment in more recent years are initiated at higher CD4 counts than in the earlier years of scale-up, and the mortality rate of those initiated has been lowered in more recent years than at the start of scale-up (Mulissa et al., 2010). Universal access to antiretroviral therapy in low-income countries can be achieved. Rwanda attained the UN threshold for universal coverage of ART of 80% in 2009, with long-term retention of care in some studies at 90% (Binagwaho et al., 2014).
However, prevention efforts must continue alongside efforts to expand treatment access (Piot et al., 2015). Anticipating now how best to deliver ART to "the ever growing cohort," in the context of decreasing donor resources, is needed. Better delivery includes enhancing simplicity, efficacy and cost effectiveness of delivery; designing simpler and cheaper ART protocols that are less toxic and easier for health services and patients; piloting innovative service delivery outside of health services, with community or expert patient-based models; and understanding how to address the gendered dimensions of treatment access and adherence (Zachariah et al., 2011b). Remuneration for lay workers in communities is also required (Decroo et al., 2014). Other structural challenges in resource-limited settings include distances to clinics, waiting lines, and drug stockouts. In recent years between 30% and 45% of low- and middle-income countries reported annual ART stock outs (WHO, 2014a). Without adequate infrastructure, the likelihood of developing resistance is increased (Gallant et al., 2013).
How to integrate HIV care into accessible, nonstigmatizing services within national health systems including for people with HIV and TB or Hepatitis C co-infections remains an ongoing challenge. [See also Preventing, Detecting and Treating Critical Co-Infections] Concerns have been raised that HIV efforts may shift scarce resources away from other urgent health priorities, rather than create a synergistic effect. "It is still common in Africa to see newly constructed, well-staffed HIV clinics side by side with crumbling primary health care facilities, with little integration and few linkages between services" (Pfeiffer et al., 2010: 2). But integration of HIV care services into primary care systems can simultaneously strengthen both HIV services and the broader system in which these services are embedded. For example, an analysis of 1,538,612 adults, including 60,303 deaths from 41 surveys in 27 countries found that between 2004 and 2008, all-cause mortality declined more in countries which were the focus of PEPFAR efforts (Bendavid et al., 2012a), though "ongoing research is needed to identify best-practice service delivery models" (Filler et al., 2011: e1). [See also Structuring Health Services to Meet Women’s Needs] All those millions of people who do get on treatment will need to continue being treated, cared for and supported for many decades to come (IOM, 2013).
Better systems are needed to reduce attrition (Zachariah et al., 2011a): tracking those who are alive and on therapy; dead; stopped treatment; transferred to another facility; and those who were lost to follow up is vital to gauge program success. A study that assessed outcomes for patients lost to follow up and who were then tracked in 17 studies from sub-Saharan Africa found that combined mortality was 46% (Brinkhof et al., 2009). Uninterrupted ART drug supplies are essential. Linking the data system with drug forecasting and procurement is also needed.
This is a brief overview of key areas in HIV treatment and service delivery and is not meant to provide treatment guidelines. [See WHO, 2013 guidelines available at http://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf?ua=1] New WHO guidelines, expected to be released in December 2015, will update the guidance from 2013 and include new areas such as the use of laboratory diagnostics, improving the quality of care, treatment of other co-morbidities and treatment and delivery of HIV care for adolescents.