Study Designs in HIV Research

Colette Smith (based on slides from Fiona Lampe)

UK CAB meeting Thursday 17th August 2017 Main types of research studies

Cross-sectional Ecological Observational Cohort

Case-control Systematic review of observational studies

Experimental Randomised controlled trial (RCT) (Intervention) Non randomised intervention study

Systematic review of experimental studies 2 Research queson and study design

• A research queson always relates to a specific populaon • Different study designs are suited to different types of research queson • Oen several study designs can be used to provide evidence to answer a specific queson

Does male circumcision influence the risk of acquision of HIV infecon? 3 Exposures and Outcomes

EXPOSURE EFFECT OUTCOME (also referred to as “risk/ (typically disease) protecve factor”; or it could be an intervenon)

Does male circumcision influence the risk of acquision of HIV infecon, among men in countries with high levels of HIV?

What is the exposure, outcome, and populaon of interest, in this research queson? 4 Session Overview

• Ecological study • Cross seconal study • Cohort study • Case-control study • Randomized controlled trial • Systemac review of RCTs

5 Ecological study

• Values available are for a populaon, country or group, not an individual • All factors measured on groups rather than individuals (unlike all other major study designs) • Data cannot be broken down to the level of the individual • Also somemes called correlaon or geographical studies • Can include comparisons over me (me series)

6 Ecological study: Male circumcision and HIV in 37 African countries (Bongaart AIDS 1989)

25 Each point on the graph represents a 20 different African country

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10

5

0

Prevalence (%) of HIV in country Prevalencein HIV (%)of 0 20 40 60 80 100 Prevalence of circumcision (%) among men in each country 7 Features of ecological studies

• Relavely quick and inexpensive, as generally use exisng data • Oen used for inial generaon of ideas, before other types of studies are undertaken • Difficult to establish “cause and effect” • Lack of individual level data, so large potenal for confounding • Major problem in interpreng results of ecological studies is the Ecological fallacy: extrapolang results from groups to individuals is problemac 8 Session Overview

• Ecological study • Cross seconal study • Cohort study • Case-control study • Randomized controlled trial • Systemac review of RCTs

9 Cross-seconal study

• A group of people are studied at a single point in me; it is a “snap shot” of the current state of affairs • Always observaonal • All factors are measured at this me point: there is no follow-up • Used primarily to assess prevalence of disease and compare between different groups • May involve quesonnaire and/or clinical measurements and tests 10 Cross-seconal study: Factors associated with HIV infecon in Rakai, Uganda (Serwadda AIDS 1992)

• Sample of 1292 adults from 21 communies in Rakai conducted in 1989 • Interview (to assess factors related to HIV transmission) and blood test for HIV

Number of Number who were Prevalence participants HIV-positive of HIV All participants 1292 255 19.7% Men 594 88 14.8% Women 698 167 23.9% Circumcised men 80 9 11.3% Uncircumcised men 495 79 16.0% 11 Features of cross-seconal studies

• Can measure disease prevalence (current number of people with the condion of interest), but not incidence (number of new events that occur over follow-up) • Relavely quick and inexpensive to conduct • Can be used to see whether condions are more frequent in one group than in another, but may be difficult to establish cause and effect (exposure and outcome measured at same me) • As with all observaonal studies, relaonship between exposure and outcome may be distorted by confounding factors

12 Session Overview

• Ecological study • Cross seconal study • Cohort study • Case-control study • Randomized controlled trial • Systemac review of RCTs

13 Cohort study

Group of people without disease

Study start

Follow-up all participants over time

Time 14 Cohort study Group exposed to the factor

Group of people without disease

Group NOT exposed to the factor

Study start

Follow-up all participants over time

Time Determine exposure status 15 Cohort study Develop disease Group exposed to the factor Do not develop disease Group of people without disease Develop disease Group NOT exposed to the factor Do not develop disease Study start

Follow-up all participants over time

Time Determine Compare occurrence of exposure status disease between exposed 16 and unexposed groups Cohort study Cohort study: Male circumcision and HIV in Rakai district (Gray AIDS 2004) n=18 acquired HIV N=908 were circumcised n=890 did not acquire HIV N=5,516 men without HIV n=154 acquired HIV N=4,608 were uncircumcised Study start n=4,454 did not acquire HIV Determine exposure status Time 2 years of follow-up 17 Cohort study Cohort study: Male circumcision and HIV in Rakai district (Gray AIDS 2004)

Circumcised Uncircumcised Number of men at start of study 908 4608 Number who developed HIV 18 154 during follow-up

(Incidence) Risk of HIV infecon 18 / 908 = 2.0% 154 / 4608 =3.3% over the 2 year period

18 Features of cohort studies

• Parcipants classified on the basis of their exposure (risk factor) status, and followed-up (“longitudinal”) to determine who develops the outcome • Can calculate and compare incidence of outcome in the exposed and unexposed groups • Can make some aempts at determining cause-and-effect/ temporality: direcon of associaon between exposure and disease is known (exposure precedes disease onset) • Large numbers of parcipants needed, especially if disease is relavely rare; me-consuming and expensive • As with all observaonal studies, associaons may be distorted by confounding factors 19 Session Overview

• Ecological study • Cohort study • Case-control study • Systemac review of observaonal studies • Randomized controlled trial • Cross seconal study

20 Case-control study

Group of people with disease: CASES

Group of people WITHOUT disease: CONTROLS Study start

Look back to determine exposure status IN THE PAST

Time Select cases and controls on the basis of disease 21 status Case-control study Group exposed to the factor Group of people with disease: Group NOT exposed to CASES the factor

Group exposed to the factor Group of people WITHOUT disease: Group NOT exposed to CONTROLS the factor Study start

Look back to determine exposure status IN THE PAST

Compare frequency of Time Select cases and controls exposure between on the basis of disease 22 cases and controls status Case-control study: Male circumcision and HIV in Abidjan, Ivory Coast (Sassan-Morokro JAIDS 1996)

415 / 490 Circumcised (n=415) CASES = 85% (HIV-posive men): NOT circumcised n=490 (n=75)

221 / 239 Circumcised (n=221) = 93% CONTROLS (HIV-negave men): NOT circumcised n=239 (n=18) Study start: Compare frequency of Look back to determine Select cases and controls exposure between on the basis of disease exposure 23 cases and controls status Features of case-control studies

• Parcipants selected on the basis of their outcome (“cases” if they have the condion; “control” if they have not) and compared with respect to previous exposure. • Well suited to studying rare diseases (select cases first) • Usually less expensive and quicker than cohort study (fewer parcipants needed and no follow-up involved) • Potenal for recall error / bias in determining exposures • As with all observaonal studies, there may be confounding 24 Confounding in observaonal studies

• Confounding is a major problem in observaonal studies • A confounder is a factor that is associated with the exposure and with the outcome • Confounders can distort the relaonship between exposure and outcome

Exposure Outcome

Confounder

25 Confounding in observaonal studies

• Confounding is a major problem in observaonal studies • A confounder is a factor that is associated with the exposure and with the outcome • Confounders can distort the relaonship between exposure and outcome

Absence of male HIV infection circumcision

26 Ecological study: Male circumcision and HIV in 37 African countries (Bongaart AIDS 1989)

25 Rwanda 20 Uganda Zambia Eastern Africa 15 Burundi

Northern Africa 10 Malawi (Egypt , Morocco, Guinea Bissau Ivory Coast Tunisia, Sudan (N)) 5 Ghana Tanzania 0

Prevalence (%) of HIV in country Prevalencein HIV (%)of 0 20 40 60 80 100 Prevalence of circumcision (%) among men in each country 27 Confounding in observaonal studies

• Confounding is a major problem in observaonal studies • A confounder is a factor that is associated with the exposure and with the outcome • Confounders can distort the relaonship between exposure and outcome

Absence of male HIV infection circumcision

Religion

28 Confounding in observaonal studies

• Confounders in associaon between circumcision and HIV include religion, ethnicity, age • In addion to simple ‘unadjusted’ analyses, adjusted analysis can be performed to control for confounding factors, using a stascal model • Associaon between lack of circumcision and HIV in observaonal studies was generally found to be at least as strong in adjusted analyses • But difficult to measure and adjust for all possible confounding factors

29 Systemac review of observaonal studies: Male circumcision and risk of HIV among men in sub- Saharan Africa (Weiss AIDS 2000)

‖ “Randomised controlled trials of male circumcision are needed (in areas where it would be acceptable to the local community). ‖ Such trials would overcome the limitaons of observaonal studies, and provide reliable evidence on the overall impact of introducon of male circumcision on HIV incidence”.

30 Session Overview

• Ecological study • Cross seconal study • Cohort study • Case-control study • Randomized controlled trial • Systemac review of RCTs

31 Randomized controlled trial

Group of people without disease

Study start

Follow-up all parcipants over me

Time 32 Randomized controlled trial

INTERVENTION group Group of people without disease CONTROL group (does NOT receive intervenon)

Study start

Follow-up all parcipants over me

Time RANDOMLY ALLOCATE each parcipant to intervenon group or control group 33 Randomized controlled trial

Develop disease INTERVENTION group Do not develop disease Group of people without disease Develop disease CONTROL group (does NOT receive intervenon) Do not develop disease Study start

Follow-up all parcipants over me

RANDOMLY ALLOCATE each Compare occurrence of Time disease between parcipant to intervenon group 34 or control group exposed and unexposed groups RCT of male circumcision for HIV prevenon, in Rakai district, Uganda (Gray et al, Lancet 2007)

N=22 N=2,387 acquired HIV immediate circumcision N=2,365 did not N=4,817 acquire HIV uncircumcised men without HIV N=45 N=2,430 acquired HIV delayed circumcision Study start N=2,385 did not RANDOMLY ALLOCATE acquire HIV each parcipant to intervenon group or control group Time Follow-up all parcipants over 2 years 35 Cohort study RCT of male circumcision for HIV prevenon, in Rakai district, Uganda (Gray et al, Lancet 2007)

INTERVENTION: CONTROL: circumcision No circumcision Number of men at start of study 2387 2430 Number who developed HIV 22 45 during follow-up

(Incidence) Risk of HIV infecon 22 / 2387 = 0.92% 45 / 2430 = 1.9%

36 Features of randomized controlled trials

• Parcipants randomly allocated to either the intervenon group or the control group: should ensure two groups have similar characteriscs at start of trial (i.e. no confounding) • Presence of a control group (usually receive the current “gold standard treatment) to act as a comparison • Individuals are followed up to determine who develops disease (i.e. longitudinal study), so RCTs usually invesgate incidence • Aim is to treat both groups idencally, so that any difference in outcome between intervenon and control groups must be due to the intervenon, rather than some other factor • Feasibility and ethical issues may prevent RCT being done 37 Session Overview

• Ecological study • Cross seconal study • Cohort study • Case-control study • Randomized controlled trial • Systemac review of RCTs

38 Systemac review of RCTs: Male circumcision and risk of heterosexual HIV acquision among men (Siegfried Cochrane Database of Systemac Reviews 2009) • Studies published up to June 2007 • 3 large RCTs were found including around 11,000 parcipants in total • They concluded “There is strong evidence that medical male circumcision reduces the acquision of HIV by heterosexual men by between 38% and 66% over 24 months.”

39 Type of study and strength of evidence Type of study and strength of evidence Strength of evidence for causal associaon between an exposure and a disease outcome

Systemac review of RCTs Strongest evidence

RCT Systemac review of observaonal studies Non randomized intervenon study Cohort study

Case-control study

Cross seconal survey

Ecological study Weakest evidence 40 Accumulaon of evidence Studies invesgang the relaonship between male circumcision and the risk of HIV acquision

Ecological study in 37 African Case-control study in Cohort study of in Systemac countries Abidjan, Ivory Coast Rakai district review of RCTs (Bongaart et al) (Sassan-Morokro et al) (Gray et al) (Siegfried et al) Cross-seconal study of factors Systemac review of associated with HIV observaonal studies infecon, in Rakai in sub-Saharan Africa RCT in Rakai (Serwadda et al) (Weiss et al) (Gray et al)

Year of publicaon 41 Accumulaon of evidence

1994: “There may be an associaon between male circumcision and risk for HIV infecon, but considerable scepcism remains” (Moses et al, AIDS)

2000: “There is considerable evidence supporng a protecve effect of male circumcision on HIV-infecon in men” (van Dam et al, Horizons Project)

2007: “Circumcision reduces risk of HIV infecon and can be recommended for HIV prevenon in men” (Gray et al, Lancet)

42 On-going issues and quesons

43 Which study design?

• For individuals currently with a CD4 count>500 cells/mm3, would it be beer to start HIV-treatment immediately, or wait unl the CD4 count reaches 350 cells/mm3? • Do previously anretroviral-naïve individuals starng an anretroviral regimen containing a new protease inhibitor have a beer response than those receiving a standard of care regimen? • Does alcohol consumpon have an impact on future development of depression in HIV-posive individuals? • Do individuals co-infected with TB and HIV have a similar first- line response to anretroviral therapy compared to individuals who are HIV-posive but do not have TB? 44