Antiretroviral Therapy to Treat HIV/AIDS | GiveWell

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Antiretroviral Therapy to Treat HIV/AIDS

This is an interim intervention report. We have spent limited time to form an initial view of this program and, at this point, our views are preliminary. We plan to consider undertaking additional work on this program in the future.

Summary

  • What is the program? Antiretroviral therapy (ART) is the use of multiple antiretroviral drugs to treat HIV infection.
  • What is its evidence of effectiveness? ART increases life expectancy when patients adhere to the treatment regimen. There is strong evidence that ART also reduces the risk of HIV transmission. We have not yet seen evidence that ART programs supported by charities are successful at ensuring patient adherence to ART or reducing mortality.
  • How cost-effective is it? Our initial cost-effectiveness estimate suggests that ART would be in the range of cost-effectiveness of our current top charities and other priority programs. We have a number of outstanding questions about the assumptions informing this estimate.
  • Does it have room for more funding? The intervention appears to have substantial room for more funding.
  • Bottom line: We would consider revisiting this intervention if we found a particular giving opportunity with robust monitoring data demonstrating high levels of adherence to ART, or strong causal evidence showing a large reduction in mortality.


Published: May 2017 (2009 version)

What is the problem?

Human immunodeficiency virus (HIV) is a virus which weakens the immune system, making infections more likely. HIV is transmitted through sexual intercourse, blood, breastfeeding or birth.1

Immune function is most often measured by CD4 cell count2 (CD4 cells are white blood cells that protect the body from infection).3 A healthy person typically has a CD4 cell count of 500 cells/mm3 to 1,600 cells/mm3.4 Patients with HIV are diagnosed with acquired immune deficiency syndrome (AIDS) when a blood test shows their CD4 cell count is below 200 cells/mm3, or they are diagnosed with an AIDS-defining illness.5

Untreated, HIV usually progresses to AIDS in 2-15 years.6 People typically die about three years after contracting AIDS.7

The World Health Organization (WHO) estimates that in 2015:

  • There were 36.7 million people living with HIV.8
  • Sub-Saharan Africa was the most affected region, with 25.6 million people living with HIV.9
  • 940,000-1.3 million people died from HIV-related causes.10

What is the program?

HIV is diagnosed by measuring CD4 count, HIV viral load, or the presence of antibodies the body produces to fight the virus.11 Antiretroviral therapy (ART) is the use of multiple antiretroviral drugs to treat HIV.12 There are six classes of antiretroviral drug commonly used in ART.13 ART does not cure HIV; rather, it aims to increase life expectancy,14 and reduce transmission rates15 by reducing viral load and increasing CD4 count.16

Does the program have strong evidence of effectiveness?

Does ART reduce the risk of HIV progressing to AIDS?

The National Institutes of Health (NIH) recommends that all HIV patients start ART immediately after diagnosis to reduce progression of the disease to AIDS.17 NIH states that "randomized controlled trials now definitively demonstrate that ART should be initiated in all HIV-infected patients, regardless of disease stage."18 We have not reviewed the two RCTs19 cited by NIH in support of their recommendation.

Does ART reduce the risk of HIV transmission?

Sexual transmission

Anglemyer et al. 2013, a Cochrane systematic review of one RCT and nine observational studies, found that ART substantially reduced sexual transmission of HIV in couples where one partner had the virus and the other did not.20

  • The one RCT in the systematic review, Cohen 2011, included 1,750 participants in nine countries.21 The rate ratio for HIV transmission reported in Anglemyer et al. 2013 was 0.04 (95% CI 0.00, 0.27)22 after 1.7 years23 (details in footnote).24 This implies a 96% reduction in incidence of HIV in sexual partners.
  • The summary rate ratio for the nine observational studies was 0.58 (95% CI 0.35, 0.96).25 When two studies were excluded for inadequate data, the summary rate ratio was 0.36 (95% CI 0.17, 0.75).26 Summaries of the individual observational studies are in this footnote.27 We have not yet reviewed these studies in detail.

We are uncertain which of these rate ratios would be a more accurate estimate of the effect of ART on reducing sexual transmission of HIV.

Mother-to-child transmission

A 2011 Cochrane systematic review on the effectiveness of ART at decreasing mother-to-child transmission of HIV concluded that "short courses of certain antiretroviral drugs are effective in reducing mother-to-child
transmission of HIV."28 The review included three RCTs comparing ART to placebo in breastfeeding populations, and three RCTs comparing ART to placebo in non-breastfeeding populations. It appears that effects varied considerably between treatment regimens, but studies of the most effective regimens found that children of treated mothers were ~30-70% less likely to have HIV at 18-month follow-up.29 We have not yet vetted the individual studies.

Do patients adhere to ART?

Strict adherence to ART is important to reduce risk of drug resistance, maintain CD4 counts, and reduce transmission.30 There appears to be some evidence that ART programs can be delivered by non-doctors without reducing levels of adherence. We would not be confident that a particular ART program was achieving high levels of adherence unless reliable monitoring of adherence was conducted for that program.

  • Kredo et al. 2014, a Cochrane systematic review, includes four RCTs and six observational studies comparing mortality between ART delivered by doctors and non-doctors.31 It concludes: "Our review found moderate quality evidence that shifting responsibility from doctors to adequately trained and supported nurses or community health workers for managing HIV patients probably does not decrease the quality of care and, in the case of nurse initiated care, may decrease the numbers of patients lost to follow-up."32 We have not yet reviewed the studies included in the review.
  • Mills et al. 2006 was the only meta-analysis we found of adherence to ART. It examines adherence to ART in North America and Africa, and identifies 27 studies in Africa which collected data on adherence outcomes.33 Pooling the results of these 27 studies, Mills et al. 2006 estimates 77% of patients adhered to ART.34 We are unsure how to interpret these results. 66% of the African studies asked patients to self-report adherence,35 which might overestimate true adherence. We also think it is possible that patients on programs with high adherence are more likely to be enrolled in studies. We have not yet reviewed the methodology of the meta-analysis in detail, or searched for more recent studies on adherence rates.

How cost-effective is it?

We created a rough cost-effectiveness estimate for this program (see ART cost-effectiveness analysis), relying on estimates of HIV mortality with and without ART in Uganda, and cost estimates from Botswana.

Using these assumptions, ART would be in the range of cost-effectiveness of our our current top charities and other priority programs.

In our experience, when we eventually identify and recommend a charity implementing a program, the cost per person reached is often significantly higher than it appeared in our preliminary estimates.

Note that our cost-effectiveness analyses are simplified models that do not take into account a number of factors. There are limitations to this kind of cost-effectiveness analysis, and we believe that cost-effectiveness estimates such as these should not be taken literally, due to the significant uncertainty around them. We provide these estimates (a) for comparative purposes and (b) because working on them helps us ensure that we are thinking through as many of the relevant issues as possible.

Major uncertainties in our model include:

  • Cost per person. The Center for Global Development cites the Botswana National AIDS Coordinating Agency as estimating per person annual costs of $480 in 2014.36 We have not been able to locate the original source for this estimate. The Botswana Ministry of Health estimates per person annual treatment costs as $357 in 2011.37 We have used the more recent $480 per person estimate, but we are unsure how accurate this is, or whether it would be representative of programs in other countries.
  • Increase in life expectancy due to receiving ART. We have not found any RCTs directly examining the effect of ART on morbidity or mortality in low-income settings versus no treatment.38 Our best guess is that ART increases life expectancy by about 18 years compared to no treatment, but we have not yet investigated this question in detail. Our current estimate comes from comparing a cohort study of the life expectancy of patients receiving ART in Uganda, with a cohort study of the life expectancy of untreated patients in Uganda before ART was rolled out (details in footnote).39 We have not investigated these two studies in detail, and it is likely that other factors affected the difference in life expectancy.
  • Disease transmission dynamics. Our best guess is that patients receiving ART will, on average, pass on their infection 75% less often than untreated people with HIV.40 This estimate does not account for potential exogenous changes in HIV incidence over time, or the long run effect of reducing HIV prevalence on HIV incidence.41
  • Moral weights. Our cost-effectiveness estimate includes difficult judgments about the moral weight of providing ART to a person with HIV relative to other good outcomes.

Does the program have room for more funding?

We think it is likely that ART has substantial room for more funding. World Health Organization estimates that 18.2 million out of 36.7 million people living with HIV received ART in 2016.42

Organizations that implement this program

We have not attempted to identify all organizations that implement ART. We are aware that Partners in Health has an ART program.43

Our process

We reviewed Cochrane systematic reviews with the search term "antiretroviral therapy" and conducted a brief literature review on Google Scholar for the search terms “antiretroviral therapy life expectancy”, “antiretroviral therapy randomized controlled trial” and "antiretroviral therapy cost-effectiveness". We also reviewed the case study of ART in Botswana in Millions Saved and sections of the WHO and CDC websites on HIV/AIDS.

Sources

Document Source
AIDS.gov, CD4 fact sheet Source (archive)
Anglemyer et al. 2013 Source (archive)
Antiretroviral Therapy Cohort Collaboration 2008 Source (archive)
ART cost-effectiveness analysis Source
Bertozzi et al. 2006 Source (archive)
Botswana Ministry of Health, Masa Analysis Source (archive)
CDC HIV Fact Sheet Source (archive)
Cohen 2011 Source (archive)
Dutta, Barker and Kallarakal 2015 Source (archive)
Johnson et al. 2013 Source (archive)
Kahn et al. 2011 Source (archive)
Kredo et al. 2014 Source (archive)
Millions Saved, ART in Botswana Source (archive)
Mills et al. 2006 Source (archive)
Mills et al. 2011 Source (archive)
Mirelman, Glassman and Temin 2016 Source (archive)
Murray 2015 Source (archive)
Murray et al. 2014 Source (archive)
NIH, ART Guidelines – Adherence to ART Source (archive)
NIH, ART Guidelines – Initiation of ART Source (archive)
NIH, HIV/AIDS fact sheet Source (archive)
NIH, HIV/AIDS fact sheet – Choosing an HIV Regimen Source (archive)
Partners in Health, HIV/AIDS Source (archive)
Rutherford, Sangani and Kennedy 2003 Source (archive)
Siegfried et al. 2011 Source (archive)
Teeraananchai et al. 2016 Source (archive)
Van der Paal et al. 2007 Source (archive)
Vella et al. 2012 Source (archive)
WHO, HIV diagnostics Source (archive)
WHO, HIV/AIDS Fact Sheet Source (archive)
World Bank Analytical Classifications Source
  • 1.

    "HIV can be transmitted via the exchange of a variety of body fluids from infected individuals, such as blood, breast milk, semen and vaginal secretions. Individuals cannot become infected through ordinary day-to-day contact such as kissing, hugging, shaking hands, or sharing personal objects, food or water." WHO, HIV/AIDS Fact Sheet

  • 2.

    "Immune function is typically measured by CD4 cell count." WHO, HIV/AIDS Fact Sheet

  • 3.

    "CD4 cells (often called T-cells or T-helper cells) are a type of white blood cells that play a major role in protecting your body from infection. They send signals to activate your body’s immune response when they detect “intruders,” like viruses or bacteria." AIDS.gov, CD4 fact sheet

  • 4.

    "The CD4 count of a healthy person ranges from 500 to 1,600 cells/mm3." NIH, HIV/AIDS fact sheet

  • 5.

    "People are diagnosed with AIDS when their CD4 cell count drops below 200 cells/mm or if they develop certain opportunistic illnesses." CDC HIV Fact Sheet

  • 6.

    "The most advanced stage of HIV infection is Acquired Immunodeficiency Syndrome (AIDS), which can take from 2 to 15 years to develop depending on the individual. AIDS is defined by the development of certain cancers, infections, or other severe clinical manifestations." WHO, HIV/AIDS Fact Sheet

  • 7.

    "Without treatment, people with AIDS typically survive about 3 years." CDC HIV Fact Sheet

  • 8.

    "There were approximately 36.7 (34.0–39.8) million people living with HIV at the end of 2015 with 2.1 (1.8–2.4) million people becoming newly infected with HIV in 2015 globally." WHO, HIV/AIDS Fact Sheet

  • 9.

    "Sub-Saharan Africa is the most affected region, with 25.6 (23.1–28.5) million people living with HIV in 2015. Also sub-Saharan Africa accounts for two-thirds of the global total of new HIV infections." WHO, HIV/AIDS Fact Sheet

  • 10.

    "HIV continues to be a major global public health issue, having claimed more than 35 million lives so far. In 2015, 1.1 (940 000–1.3 million) million people died from HIV-related causes globally." WHO, HIV/AIDS Fact Sheet

  • 11.

    "The WHO ART guidelines recommend a range of HIV diagnostics (HIV antibody test, CD4 cell count and HIV viral load count). In addition, WHO certifies HIV antibody tests/assays." WHO, HIV diagnostics

  • 12.

    "HIV treatment involves taking medicines that slow the progression of the virus in your body. HIV is a type of virus called a retrovirus, and the drugs used to treat it are called antiretrovirals (ARV). These drugs are always given in combination with other ARVs; this combination therapy is called antiretroviral therapy (ART)." CDC HIV Fact Sheet

  • 13.

    “HIV medicines are grouped into six drug classes according to how they fight HIV. The six drug classes are:

    • Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
    • Nucleoside reverse transcriptase inhibitors (NRTIs)
    • Protease inhibitors (PIs)
    • Fusion inhibitors
    • CCR5 antagonists (CCR5s) (also called entry inhibitors)
    • Integrase strand transfer inhibitors (INSTIs)

    In general, a person's first HIV regimen includes two NRTIs plus an INSTI, an NNRTI, or a PI boosted with cobicistat (brand name: Tybost) or ritonavir (brand name: Norvir). Cobicistat or ritonavir increase (boost) the effectiveness of the PI.” NIH, HIV/AIDS fact sheet – Choosing an HIV Regimen

  • 14.

    "Combination therapy with multiple antiretroviral drugs is associated with prolonged survival. Whereas monotherapies are associated with one year or less of additional survival, the survival benefit conferred by combination therapy appears to be sustainable for extended periods (Palella and others 2003). Long-term toxicities related to treatment may include athero- sclerosis, lipodystrophy, hepatic failure, and cardiac failure. Researchers are still evaluating the effects of these toxicities on HIV/AIDS mortality." Bertozzi et al. 2006, Pg 355.

  • 15.

    “Use of antiretroviral therapy. Evidence indicates that the provision of antiretroviral drugs to infected mothers significantly reduces vertical transmission (see table 18.4). The provision of antiretroviral therapy to prevent MTCT is highly cost-effective, to the point of being cost-saving for women who already know that they are infected. When screening of women is involved, cost-effectiveness declines as HIV prevalence falls, because of the larger number of women who must be screened to identify an HIV-positive woman (Rely and others 2003).” Bertozzi et al. 2006, Pg 345.

  • 16.

    "Antiretroviral therapy is effective in reducing viral load and partially enabling immune restoration, thereby preventing the onset and recurrence of opportunistic infections. If taken strictly according to directions, antiretroviral therapy can induce a sustained recovery of CD4 cell reactivity against opportunistic pathogens in severely immunosuppressed patients (Li and others 1998). The effectiveness of antiretroviral therapy is determined by its ability to rapidly reduce viral load and to sustain low levels of viral activity. This viral activity is what has an independent effect on increasing or decreasing susceptibility to opportunistic infections (Kaplan and others 2001)." Bertozzi et al. 2006, Pg 354.

  • 17.

    "Antiretroviral therapy (ART) is recommended for all HIV-infected individuals, regardless of CD4 T lymphocyte cell count, to reduce the morbidity and mortality associated with HIV infection (AI)." NIH, ART Guidelines – Initiation of ART

  • 18.

    NIH, ART Guidelines – Initiation of ART

  • 19.

    "Most recently, the published START and TEMPRANO trials provide the evidence for the Panel’s recommendation to initiate ART in all patients regardless of CD4 cell count (AI). The results of these two studies are summarized below.

    The START trial is a large, multi-national, randomized controlled clinical trial designed to evaluate the role of early ART in asymptomatic HIV-infected patients in reducing a composite clinical endpoint of AIDS-defining illnesses, serious non-AIDS events, or death. In this study, ART-naive adults (aged >18 years) with CD4 counts >500 cells/mm3 were randomized to initiate ART soon after randomization (immediate-initiation arm) or to wait to initiate ART until their CD4 counts declined to <350 cells/mm3 or until they developed a clinical indication for therapy (deferred-initiation arm). The study enrolled 4,685 participants, with a mean follow-up of 3 years. When the randomized arms of the study were closed, the primary endpoint of serious AIDS or non-AIDS events was reported in 42 participants (1.8%, or 0.60 events/100 person-years) in the early ART arm and 96 participants (4.1%, or 1.38 events/100 person-years) in the deferred ART arm (hazard ratio [HR] 0.43, favoring early ART [95% confidence interval (CI), 0.30–0.62, P < .001]). The most common clinical events reported were tuberculosis and AIDS and non-AIDS malignancies. The majority (59%) of clinical events in the delayed ART arm occurred in participants whose CD4 counts were still above 500 cells/mm3, evidence for a benefit of immediate ART even before CD4 count declines below this threshold. Furthermore, the benefit of immediate ART was evident across all participant subgroups examined including men and women, older and younger participants, individuals with high and low plasma HIV RNA levels, and participants living in high-income and low/middle-income countries. Although START was not sufficiently powered to examine the benefit of immediate ART for each category of clinical events, the benefit of immediate ART appeared to be particularly strong for AIDS events (HR 0.28, [95% CI, 0.15–0.50, P < .001]), tuberculosis (HR 0.29, [95% CI, 0.12–0.73, P = .008]), and malignancies (HR 0.36, [95% CI, 0.19 to 0.66; P = .001]). Importantly, immediate ART also significantly reduced the rate of pooled serious non-AIDS events (HR 0.61, [95% CI, 0.38–0.97, P = 0.04]).

    The TEMPRANO ANRS 12136 study was a randomized controlled trial conducted in Cote d’Ivoire. Using a two-by-two factorial design, HIV-infected participants with CD4 counts <800 cells/mm3 were randomized to either immediate ART or deferred ART (based on the national guidelines criteria for starting treatment); half of the participants in each group received isoniazid for prevention of tuberculosis for 6 months and half did not. The primary study endpoint was a combination of all-cause deaths, AIDS diseases, non-AIDS malignancies, and non-AIDS invasive bacterial diseases. More than 2,000 participants enrolled in the trial, with a median follow-up of 30 months. Among the 849 participants who had baseline CD4 counts >500 cells/mm3, 68 primary outcome events were reported in 61 patients. The risk of primary events was lower with immediate ART than with deferred ART, with a hazard ratio of 0.56 in favor of early ART (CI, 0.33–0.94). On the basis of these results, the study team concluded that early ART is beneficial in reducing the rate of these clinical events.

    The TEMPRANO and START trials had very similar estimates of the protective effect of immediate ART among HIV-infected individuals with CD4 counts >500 cells/mm3, further strengthening the Panel’s recommendation that ART be initiated in all patients regardless of CD4 cell count." NIH, ART Guidelines – Initiation of ART

  • 20.

    “ART is a potent intervention for prevention of HIV in discordant couples in which the index partner has ≤550 CD4 cells/µL. A recent multicentre RCT confirms the suspected benefit seen in earlier observational studies and reported in more recent ones. Questions remain about durability of protection, the balance of benefits and adverse events associated with earlier therapy, long-term adherence and transmission of ART-resistant strains to partners. Resource limitations and implementation challenges must also be addressed.” Anglemyer et al. 2013

  • 21.

    "This was a Phase III, two-arm, multicentre RCT that enrolled 1750 serodiscordant heterosexual and male homosexual couples. All index cases had 350-550 CD4 cells/µL at baseline and were randomly assigned to immediate ART treatment initiation or delayed treatment until two consecutive measurements of 200-250 CD4 cells/µL or an AIDS defining illness (HPTN 2011). No participants had histories of injection drug use. All serodiscordant couples were given prevention and adherence counseling and provided with free condoms. In the immediate treatment arm over 1585 person years, there was one HIV transmission to partner that was linked by virological genomic analysis to that of the index case. In the delayed treatment arm over 1567 person years, there were 27 linked HIV transmissions, yielding a rate ratio of 0.04 (95% CI 0.00-0.27). When considering all HIV infections, regardless of confirmatory linkages, there were 35 HIV transmissions in the delayed arm and 4 transmissions in the immediate arm (rate ratio 0.11; 95% CI 0.04-0.32)." Anglemyer et al. 2013

  • 22.

    “The rate ratio for the single randomised controlled trial was 0.04 [95% CI 0.00, 0.27]” Anglemyer et al. 2013

  • 23.

    "On April 28, 2011, the data and safety monitoring board recommended that the results of the study be released on the basis of data collection through February 21, 2011. At that time, 90% of couples remained enrolled in the study, with a median follow-up of 1.7 years" Cohen 2011

  • 24.

    "Cohen 2011: This was a Phase III, two-arm, multicentre RCT that enrolled 1750 serodiscordant heterosexual and male homosexual couples. All index cases had 350-550 CD4 cells/µL at baseline and were randomly assigned to immediate ART treatment initiation or delayed treatment until two consecutive measurements of 200-250 CD4 cells/µL or an AIDS defining illness (HPTN 2011). No participants had histories of injection drug use. All serodiscordant couples were given prevention and adherence counseling and provided with free condoms. In the immediate treatment arm over 1585 person years, there was one HIV transmission to partner that was linked by virological genomic analysis to that of the index case. In the delayed treatment arm over 1567 person years, there were 27 linked HIV transmissions, yielding a rate ratio of 0.04 (95% CI 0.00-0.27). When considering all HIV infections, regardless of confirmatory linkages, there were 35 HIV transmissions in the delayed arm and 4 transmissions in the immediate arm (rate ratio 0.11; 95% CI 0.04-0.32). Subsequent analyses identified 38 cases, from which 29 (76.3%) were definitively linked using a phylogenetic analysis of HIV pol sequences, and in 7 cases (18.4%) the index partner was ruled out as a likely source of HIV infection (Eshleman 2011)." Anglemyer et al. 2013

  • 25.

    "Similarly, the summary rate ratio for the nine observational studies was 0.58 [95% CI 0.35, 0.96], with substantial heterogeneity (I2=64%)." Anglemyer et al. 2013

  • 26.

    "After excluding two studies with inadequate person-time data, we estimated a summary rate ratio of 0.36 [95% CI 0.17, 0.75]" Anglemyer et al. 2013

  • 27.
    • "Musicco 1994: Musicco and colleagues conducted a cohort study in Italy, which was published in 1994 in the era before the advent of combination ART. They followed a cohort of 436 monogamous HIV-uninfected female sexual partners of HIV-infected men recruited from 16 centres in Italy. Seventy-nine percent of the male index patients had histories of injection drug use, 25% had symptoms of AIDS, and 48% had fewer than 400 CD4 cells/µL. There were 27 seroconversions observed, 21 in partners of men who were not receiving AZT monotherapy and 6 in partners of men who were. Incidence in the untreated group was 4.4 per 100 person years (95% confidence interval [CI] 2.6-5.7) and 3.8 (95% CI 1.4-8.3) in the treated group (unadjusted rate ratio 0.88, 95% CI 0.36-2.16). However, when adjusted for consistent condom use, presence of p24 antigen, CD4 counts and symptoms of AIDS in infected male partners, the relative risk of female partners of men treated with AZT acquiring HIV was 50% lower (RR 0.5, 95% CI 0.1-0.9) when compared to female partners of men not treated with AZT." Anglemyer et al. 2013
    • "Melo 2008: Melo and colleagues followed a cohort of 93 discordant couples in Porto Alegre, Brazil, in which the female member of the couple was infected in 67 (72%) and the male in 26 (28%). Fifteen (58%) of the 26 male and 6 (9%) of the female index cases had histories of injection drug use. Of the 26 male index cases, 5 (19%) had CD4 counts under 350 cells/µL; of the 67 female index cases, 3 (5%) had under 350 CD4 cells/µL, and 33 (49%) were pregnant at baseline. Comparing treated to untreated serodiscordant couples, their results suggest a protective effect of ART (rate ratio=0.10; 95% CI 0.01-1.67)." Anglemyer et al. 2013
    • "Sullivan 2009: Sullivan and colleagues presented data from two cohorts of 2,993 HIV-discordant couples in Rwanda and Zambia followed from 2002 to 2008. No additional background data on cohort members were available from the conference abstract. They observed 175 new infections of which 4 were from partners of index cases on ART. Incidence density was 3.4% per 100 person-years for those whose partners were not taking ART and 0.7% for those whose partners were taking ART (rate ratio= 0.21, 95% CI 0.08-0.59). An earlier abstract also reported on this cohort (Kayitenkore 2006)." Anglemyer et al. 2013
    • "Del Romero 2010: Del Romero and colleagues analysed data from 648 heterosexual couples attending a clinic in Madrid, Spain, from 1989 to 2008, where uninfected partners were examined for prevalent HIV infection. Five hundred thirty-five (83%) of the index cases were male and 113 (17%) female. Of the 648 index cases, 494 (76%) had histories of injection drug use. Median CD4 count was 500 cells/µL. Clinical AIDS had been diagnosed at baseline in 107 (17%) of index cases. Forty-six partners were found to have prevalent HIV infection when examined prior to follow-up. Forty-four of these occurred in partners of index cases who had received no ART, and 2 were in partners of index cases who had received either monotherapy or dual therapy. Four hundred twenty-four serodiscordant couples had follow-up information collected over 1355 couple years. Five transmission events occurred in untreated couples over 863 couple years, and no transmissions occurred among treated couples over 492 couple years (rate ratio 0.21; 95% CI 0.01-3.75). Earlier studies also analysed this cohort (Castilla 2005)." Anglemyer et al. 2013
    • "Donnell 2010: Donnell and colleagues reported data in an abstract from a prospective cohort analysis of an RCT of heterosexual African adults who were seropositive for both HIV and herpes simplex virus type 2 (HSV-2) and their HIV-uninfected sexual partners. Three thousand four hundred eight couples were enrolled from seven countries (Botswana, Kenya, Rwanda, South Africa, Tanzania, Uganda and Zambia). Of the 3,381 infected index cases, 2,284 (68%) were female and 1,097 (32%) were male. The median CD4 count of index patients was 462 cells/µL, the median plasma viral load was 4.1 log10 copies/mL, and 34% of infected male partners and 55% of uninfected male partners were circumcised. One hundred three genetically linked new infections were identified in partners; one was in the partner of a treated index case. The incidence in partners of untreated index cases was 2.24 (1.84-2.72) per 100 person-years as compared to 0.37 (95% CI 0.09-2.04) per 100 person-years in partners of treated index cases (adjusted incidence rate ratio 0.08, 95% CI 0.00-0.57). This population was previously analysed in another abstract (Donnell 2009)." Anglemyer et al. 2013
    • "Lu 2010: Lu and colleagues analysed data from a prospective cohort study that enrolled 1927 heterosexual couples between January 2006 and December 2008 for testing and treatment at county hospitals in China. Serodiscordant couples were identified through an HIV database and enrolled at local hospitals and health centres. The couples received HIV testing every 6 months and in the event of transmission to an uninfected partner, a recent history of sexual behaviours was taken from the participants. Of the 1927 couples, there were 1092 (57%) HIV-infected male partners and 835 (43%) HIV-infected female partners. The last recorded CD4 count was under 200 cells/µL for 422 index spouses (23%), and ≥350 cells/µ for 675 (35%) index partners. Approximately 80% of the studied couples were treated with antiretroviral therapy. Eighty-four (4%) partners seroconverted by the end of follow up, yielding an overall rate of 1.71 per 100 person-years. There was no relationship between the rate of seroconversion and last CD4 count in the index spouse. There was also no effect of ART on preventing HIV transmission in this study as 4.8% of treated couples and 3.2% of untreated couples seroconverted (yielding a non-significant rate ratio of 1.44; 95% CI 0.85-2.44)." Anglemyer et al. 2013
    • "Reynolds 2011: Reynolds and colleagues reported data from a cohort of 250 HIV-discordant couples from Rakai, Uganda. They observed 42 seroconversions over 459 person-years of exposure to index patients not on ART (incidence 9.2 per 100 person-years, 95% CI 6.6-12.4) and none over 53.6 person-years on ART (rate ratio= 0.10; 95% CI 0.01-1.64)." Anglemyer et al. 2013
    • "Birungi 2012: Birungi and colleagues examined the effectiveness of ART as prevention in a programmatic setting in rural Uganda without access to viral load testing. The authors enrolled 550 serodiscordant couples and began HAART in 260 couples (CD4 under 250 or WHO stage IV illness) and delayed treatment in 290 couples not yet eligible for ART. All couples were tested every 3 months. Ultimately, 586 couples were enrolled with 348 couples (59%) of the positive participants received ART during the study (249 on ART at enrolment; 99 began ART after enrolment). Median ART-use at enrolment was 2.5 years among couples treated with ART. Median follow up was 1.3 years for all couples. There were 17 infections diagnosed during the follow-up (9 infections in the ART group and 8 infections in the non-ART group). Incidence was estimated as 2.09 infections per 100 person years for the ART group and 2.30 infections per 100 person years for the non-ART group. The overall incidence rate ratio was 0.91 (95% CI 0.38-2.20)." Anglemyer et al. 2013
    • "Jia 2012: This was a large, national-level study assessing the effect of antiretroviral therapy on HIV transmission risk among discordant couples across China from January 2003 to December 2011. All HIV-infected individuals in China who reported having a spouse or regular sex partner were followed by the Chinese Centre for Disease Control and Prevention (China CDC). Every 6 months HIV-negative partners were tested and HIV-infected partners received repeat CD4 cell count tests. A total of 24,057 discordant couples were identified for the ART-treated cohort and 14,805 discordant couples were identified for the ART-naive cohort and followed over 101,295.1 person-years. Over all couples, a total of 1631 HIV transmissions occurred for an overall rate of 1.6 transmission per 100 person-years (95% CI 1.5-1.7). Among treated couples, the rate was 1.3 per 100 person years (95% CI 1.2-1.3) and among the untreated couples the transmission rate was 2.6 per 100 person years (95% CI 2.4-2.8), yielding an unadjusted HR=0.61 (95% CI 0.55-0.67). After adjusting for duration of follow-up, sociodemographic variables, route of HIV infection, and baseline CD4 among index cases, the authors estimated a HR=0.74 (95% CI 0.65-0.84). Considering couples treated with baseline CD4 under 250 compared to couples untreated the unadjusted HR=0.57 (95% CI 0.45-0.72). Similarly, considering couples treated with baseline CD4 250-349 compared to couples untreated the unadjusted HR=0.66 (95% CI 0.47-0.94). Lastly, comparing couples treated with baseline CD4 350 or greater with untreated couples, HR=0.45 (95% CI 0.31-0.66)." Anglemyer et al. 2013
  • 28.

    Siegfried et al. 2011

  • 29.

    "In breastfeeding populations, three trials found that:

    ZDV given to mothers from 36 to 38 weeks gestation, during labour and for 7 days after delivery significantly reduced HIV infection at 4-8 weeks (Efficacy 32.00%; 95% CI 1.50 to 62.50), 3 to 4 months (Efficacy 33.07%; 95% CI 5.57 to 60.57), 6 months (Efficacy 34.55%; 95% CI 9.05 to 60.05), 12 months (Efficacy 34.31%; 95% CI 9.30 to 59.32) and 18 months (Efficacy 29.74%; 95% CI 2.73 to 56.75).

    ZDV given to mothers from 36 weeks gestation and during labour significantly reduced HIV infection at 4 to 8 weeks (Efficacy 43.78%; 95% CI 8.78 to 78.78) and 3 to 4 months (Efficacy 36.95%; 95% CI 2.94 to 70.96) but not at birth.

    ZDV plus lamivudine (3TC) given to mothers from 36 weeks gestation, during labour and for 7 days after delivery and to babies for the first 7 days after birth (PETRA 'regimen A') significantly reduced HIV infection (Efficacy 62.75%; 95% CI 40.76 to 84.74) and a combined endpoint of HIV infection or death (Efficacy 62.75 [, ]61.00%; 95% CI 40.76 to 84.74) at 4 to 8 weeks but these effects were not sustained at 18 months.

    ZDV plus 3TC given to mothers from the start of labour until 7 days after delivery and to babies for the first 7 days after birth (PETRA 'regimen B') significantly reduced HIV infection (Efficacy 41.83%; 95% CI 12.82 to 70.84) and HIV infection or death at 4 to 8 weeks (Efficacy 35.91%; 95% CI 8.41 to 63.41) but the effects were not sustained at 18 months.

    ZDV plus 3TC given to mothers during labour only (PETRA 'regimen C') with no treatment to babies did not reduce the risk of HIV infection at either 4 to 8 weeks or 18 months.

    In non-breastfeeding populations, three trials found that:

    ZDV given to mothers from 14 to 34 weeks gestation and during labour and to babies for the first 6 weeks after birth significantly reduced HIV infection in babies at 18 months (Efficacy 66.22%; 95% CI 33.94 to 98.50).

    ZDV given to mothers from 36 weeks gestation and during labour with no treatment to babies ('Thai-CDC regimen') significantly reduced HIV infection at 4 to 8 weeks (Efficacy 50.26%; 95% CI 13.80 to 86.72) but not at birth

    ZDV given to mothers from 38 weeks gestation and during labour with no treatment to babies did not influence HIV transmission at 6 months."
    Siegfried et al. 2011

  • 30.

    "Strict adherence to antiretroviral therapy (ART) is key to sustained HIV suppression, reduced risk of drug resistance, improved overall health, quality of life, and survival, as well as decreased risk of HIV transmission. Conversely, poor adherence is the major cause of therapeutic failure. Achieving adherence to ART is a critical determinant of long-term outcome in HIV infected patients. For many chronic diseases, such as diabetes or hypertension, drug regimens remain effective even after treatment is resumed following a period of interruption. In the case of HIV infection, however, loss of virologic control as a consequence of non-adherence to ART may lead to emergence of drug resistance and loss of future treatment options. Many patients initiating ART or already on therapy are able to maintain consistent levels of adherence with resultant viral suppression, CD4+ T-lymphocyte (CD4) count recovery, and improved clinical outcomes. Others, however, have poor adherence from the outset of ART and/or experience periodic lapses in adherence over the lifelong course of treatment. Identifying those with adherence-related challenges that require attention and implementing appropriate strategies to enhance adherence are essential roles for all members of the treatment team." NIH, ART Guidelines – Adherence to ART

  • 31.
    • "We included controlled trials (randomised or non-randomised), controlled-before and after studies, and cohort studies (prospective or retrospective) comparing doctor-led antiretroviral therapy delivery to delivery that included another cadre of health worker other than a doctor, for initiating treatment, continuing treatment, or both, in HIV infected patients." Kredo et al. 2014
    • "Ten studies met our inclusion criteria, all of which were conducted in Africa. Of these four were randomised controlled trials while the remaining six were cohort studies." Kredo et al. 2014
  • 32.

    "Ten studies met our inclusion criteria, all of which were conducted in Africa. Of these four were randomised controlled trials while the remaining six were cohort studies.

    From the trial data, when nurses initiated and provided follow-up HIV therapy, there was high quality evidence of no difference in death at one year, unadjusted risk ratio was 0.96 (95% CI 0.82 to 1.12), one trial, cluster adjusted n = 2770. There was moderate quality evidence of lower rates of losses to follow-up at one year, relative risk of 0.73 (95% CI 0.55 to 0.97). From the cohort data, there was low quality evidence that there may be an increased risk of death in the task shifting group, relative risk 1.23 (95% CI 1.14 to 1.33, two cohorts, n = 39 160) and very low quality data reporting no difference in patients lost to follow-up between groups, relative risk 0.30 (95% CI 0.05 to 1.94).

    From the trial data, when doctors initiated therapy and nurses provided follow-up, there was moderate quality evidence that there is probably no difference in death compared with doctor-led care at one year, relative risk of 0.89 (95% CI 0.59 to 1.32), two trials, cluster adjusted n = 4332. There was moderate quality evidence that there is probably no difference in the numbers of patients lost to follow-up at one year, relative risk 1.27 (95% CI 0.92 to 1.77), P = 0.15. From the cohort data, there is very low quality data that death at one year may be lower in the task shifting group, relative risk 0.19 (95% CI 0.05 to 0.78), one cohort, n = 2772, and very low quality evidence that loss to follow-up was reduced, relative risk 0.34 (95% CI 0.18 to 0.66).

    From the trial data, for maintenance therapy delivered in the community there was moderate quality evidence that there is probably no difference in mortality when doctors deliver care in the hospital or specially trained field workers provide home-based maintenance care and antiretroviral therapy at one year, relative risk 1.0 (95% CI 0.62 to 1.62), 1 trial, cluster adjusted n = 559. There is moderate quality evidence from this trial that losses to follow-up are probably no different at one year, relative risk 0.52 (0.12 to 2.3), P = 0.39. The cohort studies did not report on one year follow-up for these outcomes.

    Across the studies that reported on virological and immunological outcomes, there was no clear evidence of difference whether a doctor or nurse or clinical officer delivered therapy. Three studies report on costs to patients, indicating a reduction in travel costs to treatment facilities where task shifting was occurring closer to patients homes. There is conflicting evidence regarding the relative cost to the health system, as implementation of the strategy may increase costs. The two studies reporting the patient and staff perceptions of the quality of care, report good acceptability of the service by patients, and general acceptance by doctors of the shifting of roles. One trial reported on the time to initiation of antiretroviral therapy, finding no clear evidence of a difference between groups. The same trial reports on new diagnosis of tuberculosis which favours nurse initiation of HIV care for increasing the numbers of diagnoses of tuberculosis made." Kredo et al. 2014

  • 33.
    • Data Sources: "Eleven electronic databases were searched along with major conference abstract databases (inclusion dates: inception of database up until April 18, 2006)"
    • Study Selection and Data Abstraction: "To best reflect the general population, studies of mixed populations in both North America and Africa were selected. Studies evaluating specific populations such as men only, homeless individuals, or drug users, were excluded. The data were abstracted in duplicate on study adherence outcomes, thresholds used to determine adherence, and characteristics of the populations. A random effects meta-analysis was performed in which heterogeneity was examined using multivariable random-effects logistic regression."
    • Data Synthesis: "27 studies (9 full-text articles and 18 abstracts) from sub-Saharan Africa were included. African studies represented 12 sub-Saharan countries."

    Mills et al. 2006, Pg 679.

  • 34.

    “Our pooled analysis of African studies (12 116 patients total) indicated a pooled estimate of 77% (95% confidence interval, 68%-85%; I2, 98.4%).” Mills et al. 2006, Pg 679.

  • 35.

    "Of the North American studies, 71% used patient self-report to assess adherence; this was true of 66% of the African assessments." Mills et al. 2006, Pg 679.

  • 36.

    "In 2014, treatment costs for the national ART program were estimated at US$480 per person. This cost is expected to rise to US$600 per person by 2030, primarily due to the growing need for second- and third-line ART as the virus becomes more resistant to the first-line option." Millions Saved, ART in Botswana

  • 37.

    "The costing exercise of the Masa Programme was done from 2009-2010. This exercise estimated that the cost of treatment per patient would be $357.00 USD in 2011 and projected it to reach $430.00 USD in 2014. The estimate for the total cost of the program in 2010 added up to $53 million USD, which in 2014 is projected to reach $99 million USD. The costing exercise highlighted that the three primary drivers of the provision of ART in the Masa Programme are ART drugs, laboratory tests, and personnel." Botswana Ministry of Health, Masa Analysis, Pg 5.

  • 38.
    • We searched the Cochrane database of Systematic Reviews with the search term "antiretroviral therapy". There were 66 results. None of the systematic reviews examined the effect of ART on morbidity or mortality versus no treatment.
    • We searched Google Scholar with the search term "antiretroviral therapy randomized controlled trial" and read the abstracts of the first 200 results. None of the RCTs examined the effect of ART on morbidity or mortality in low-income settings versus no treatment.
  • 39.
    • We took the weighted average of age-specific life expectancies in Mills et al. 2011, a cohort study of patients on ART in Uganda, to estimate life-expectancy of patients receiving ART between 2002 and 2009 as 27 years. Full calculations are in ART cost-effectiveness analysis.
    • We used Van der Paal et al. 2007, a cohort study of untreated HIV-positive patients in Uganda to estimate life-expectancy of untreated patients as nine years.
      • "For incident HIV cases the median survival from seroconversion to death was 9.0 years (95% CI 7.5, 10.6)" Van der Paal et al. 2007
    • We also found Teeraananchai et al. 2016, a meta-analysis of eight cohort studies on life expectancy of HIV patients on ART (details below), which included three cohort studies in low-income settings. We decided to use the estimate in Mills et al. 2011 because, like Van der Paal et al. 2007, it was set in Uganda. We searched for, but were unable to find, estimates for life expectancy of untreated HIV patients in low-income settings other than Uganda.

    Mills et al. 2011:

    • Objective: "To estimate life expectancy of patients once they initiate cART [combination antiretroviral therapy] in Uganda."
    • Design: "Prospective cohort study."
    • Method: "Patients: 22 315 eligible patients initiated cART during the study period, of whom 1943 were considered to have died. Measurements: All-cause mortality rates were calculated and abridged life tables were constructed and stratified by sex and baseline CD4 cell count status to estimate life expectancies for patients receiving cART. The average number of years remaining to be lived by patients who received cART at varying age categories was estimated."
    • Results: "After adjustment for loss to follow-up, crude mortality rates (deaths per 1000 person-years) ranged from 26.9 (95% CI, 25.4 to 28.5) in women to 43.9 (CI, 40.7 to 47.0) in men. For patients with a baseline CD4 cell count less than 0.050 × 109 cells/L, the mortality rate was 67.3 (CI, 62.1 to 72.9) deaths per 1000 person-years, whereas among persons with a baseline CD4 cell count of 0.250 × 109 cells/L or more, the mortality rate was 19.1 (CI, 16.0 to 22.7) deaths per 1000 person-years. Life expectancy at age 20 years for the overall cohort was 26.7 (CI, 25.0 to 28.4) additional years and at age 35 years was 27.9 (CI, 26.7 to 29.1) additional years. Life expectancy increased substantially with increasing baseline CD4 cell count. Similar trends are observed for older age groups."

    Van der Paal et al. 2007:

    • Objective: "To provide estimates of survival and progression to different HIV disease endpoints after HIV infection among adults in a rural Ugandan setting."
    • Design: "A prospective population-based cohort study."
    • Methods: "Eligible individuals at least 15 years of age with documented HIV seroconversion were recruited from a general population cohort in rural Uganda, along with a randomly selected proportion of HIV-prevalent and HIV-negative individuals. All participants were followed up every 3 months, and CD4 cell counts taken every 6 months in HIV-positive participants. Life tables and Kaplan–Meier functions were used to estimate survival patterns for all endpoints [death, time to World Health Organization (WHO) stage 2, 3, AIDS and CD4 cell count Results: "We recruited 240 HIV incident cases, 108 prevalent cases and 257 HIV-negative controls. Crude mortality rates were 70.0 per 1000 person-years in HIV-positive, and 12.1 per 1000 person-years in HIV-negative individuals. The median time from seroconversion to death was 9.0 years (N = 240) and 6.2 years to a CD4 cell count less than 200 cells/μl or WHO stage 4 (N = 229). The median time from ART eligibility (CD4 cell count under 200 cells/μl, under 350 cells/μl and WHO stage 3, or WHO stage 4) to death was 34.7 months. Older age at seroconversion was a risk factor for faster progression to death and ART eligibility."

    Teeraananchai et al. 2016:

    • Objective: "The objective of our study was to perform a meta-analysis to assess life expectancy of HIV-positive people after starting cART, and to quantify differences between low/middle- and high-income countries."
    • Included studies: "The articles reported on patient cohorts from Europe [14,17], Canada [17,18], the UK [15–17], the USA [17,18], Uganda [19], South Africa [20] and Rwanda [21]. Four studies were conducted in high-income countries from 1996 to 2011 [14–18] and three studies were conducted in low/middle-income countries from 2001 to 2011 [19–21]."
    • Results: "Overall life expectancy in high-income countries was an additional 43.3 years [95% confidence interval (CI) 42.5-44.2 years] and 32.2 years (95% CI 30.9-33.5 years) at ages 20 and 35 years, respectively, and 28.3 (95% CI 23.3-33.3) and 25.6 (95% CI 22.1-29.2) additional years, respectively, in low/middle-income countries. In low/middle-income countries, life expectancy after starting cART at age 20 years was an additional 22.9 years (95% CI 18.4-27.5 years) for men and 33.0 years (95% CI 30.4-35.6 years) for women, but was similar in the two sexes in high-income countries. In all income regions, life expectancy after starting cART increased over calendar time."
  • 40.

    ART cost-effectiveness analysis

  • 41.

    We have estimated the reduction in HIV transmission from a person receiving ART. We have not estimated the impact of reducing HIV transmission from the person they would have infected.

  • 42.

    WHO, HIV/AIDS Fact Sheet

  • 43.
    • Partners in Health, HIV/AIDS
    • ”The 13th International AIDS Conference in Durban in July 2000, the first to be held in Africa, focused the world's attention on the continent most seriously affected by the AIDS epidemic. Brazil had been a pioneer among developing countries in providing treatment as early as 1996 and small-scale projects by nongovernment organizations – such as that of Partners in Health in Haiti – also showed promising results.” Vella et al. 2012