The authors have declared that no competing interests exist.
Conceived and designed the experiments: RAA TBH. Performed the experiments: RAA. Analyzed the data: RAA TBH. Contributed reagents/materials/analysis tools: JMB CLC TBH. Wrote the paper: RAA JMB CLC JPH LJA RVB TBH.
Despite demonstrating only partial efficacy in preventing new infections, available HIV prevention interventions could offer a powerful strategy when combined. In anticipation of combination HIV prevention programs and research studies we estimated the population-level impact of combining effective scalable interventions at high population coverage, determined the factors that influence this impact, and estimated the synergy between the components.
We used a mathematical model to investigate the effect on HIV incidence of a combination HIV prevention intervention comprised of high coverage of HIV testing and counselling, risk reduction following HIV diagnosis, male circumcision for HIV-uninfected men, and antiretroviral therapy (ART) for HIV-infected persons. The model was calibrated to data for KwaZulu-Natal, South Africa, where adult HIV prevalence is approximately 23%.
Compared to current levels of HIV testing, circumcision, and ART, the combined intervention with ART initiation according to current guidelines could reduce HIV incidence by 47%, from 2.3 new infections per 100 person-years (pyar) to 1.2 per 100 pyar within 4 years and by almost 60%, to 1 per 100 pyar, after 25 years. Short-term impact is driven primarily by uptake of testing and reductions in risk behaviour following testing while long-term effects are driven by periodic HIV testing and retention in ART programs. If the combination prevention program incorporated HIV treatment upon diagnosis, incidence could be reduced by 63% after 4 years and by 76% (to about 0.5 per 100 pyar) after 15 years. The full impact of the combination interventions accrues over 10–15 years. Synergy is demonstrated between the intervention components.
High coverage combination of evidence-based strategies could generate substantial reductions in population HIV incidence in an African generalized HIV epidemic setting. The full impact could be underestimated by the short assessment duration of typical evaluations.
Three decades into the fight to prevent new HIV infections, no single intervention has been found to have sufficiently high efficacy, acceptability, feasibility, and affordability to individually control the generalized HIV epidemic in sub-Saharan Africa. However, a growing number of interventions have been shown to partially reduce HIV risk and have been demonstrated to be deliverable at scale in Africa. These include reducing sexual risk behaviour by increasing condom use and decreasing partner acquisition rate, reducing the likelihood of HIV acquisition by male circumcision for HIV uninfected men
HIV testing is the crucial entry point to effective HIV prevention. For infected persons, knowledge of HIV status enables referral to care and assessment for ART. Testing can also motivate male circumcision for HIV uninfected men and reductions in risk behaviour, particularly among newly diagnosed persons with HIV
Implementation and field evaluation of wide-scale HIV testing coupled with combination HIV prevention interventions are urgently needed. Program evaluations and clinical trials are underway
Some previous model projections have suggested that ART alone could achieve high impact on HIV incidence
In this article, we use a mathematical model of the HIV epidemic in South Africa to study HIV incidence under rapid and high testing coverage that is repeated every four years and the following interventions: risk reduction following HIV diagnosis (the first HIV-positive test), medical male circumcision, and ART initiation following current WHO guidelines (CD4 count ≤350 cells/ml). First, the interventions are considered individually to disentangle and characterize their impacts. Secondly, we estimate the population-level impact of a feasible implementation of a combination intervention and examine how trials to measure these effects might be designed. Thirdly, we studied the implications of expanding ART initiation to be upon HIV diagnosis. Finally, we determine the factors that influence this impact and quantify the interaction between the components in the combined intervention at the short and the long terms. The HIV settings of South Africa are ideal for our study because of very high HIV prevalence (17% among 15–49 year-old men and women) and because trials of a combination of deliverable prevention interventions are being planned in similar settings.
We constructed a compartmental mathematical model to represent transmission of HIV in the heterosexual adult population in KwaZulu-Natal (KZN), South Africa. A full technical specification of the model and its parameterization is given in
Sources of data used to calibrate the baseline model were in A) HIV prevalence among women attending prenatal clinics
Assumption | Parameter value | Sources |
Demography and sexual behaviour | ||
|
|
|
|
|
|
|
|
|
HIV pathogenesis | ||
|
|
|
|
|
|
|
|
|
Multiplicative factor change in baseline HIV transmission probability | ||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Intervention Scenario: |
|
|
|
|
|||
Nature of testing | Continuously available via VCT | Community testing | Community testing |
Coverage of HV testing (% of eligible adults) | 20 |
90 | 90 |
Interval before reaching the above coverage level (years) | none | 1 | 1 |
Interval between rounds of testing (years) | no rounds | 4 | 4 |
|
|||
Increase in condom use (men/women) | 12.5%/6.25% |
25%/12.5% | 25%/12.5% |
Decrease in partner acquisition rate (men/women) | 12.5%/12.5% |
25%/25% | 25%/25% |
Mean duration of keeping the above behaviour changes | 1 year |
3 years | 3 years |
|
|||
Circumcision effect reducing men’s susceptibility to HIVper sex act | 60% |
60% |
60% |
Proportion of uncircumcised men that are newly circumcised (final levels are continued in the future) | 10% over 4 years | 70% over 2 years | 70% over 2 years |
|
|||
ART efficacy of reducing infectiousness | 92% |
92% |
92% |
CD4 count threshold at which tested individuals start ART | 200* | 350 |
any CD4 count |
Coverage | 52% |
100% | 100% |
Drop out rate (per year) from ART initiated at any CD4 count | 14.5% |
14.5% |
14.5% |
Representative values
Treatment initiation at HIV stages with CD4>100 cells/mm3 is immediate when the individual is aware of status and meeting the guideline and is delayed when unaware of status by an average duration that is calibrated to reflect current treatment programs
The intervention scenarios investigated focused on three partially-effective HIV interventions and were based on achieving 90% HIV testing of adults over one year (for example through community home based counselling and testing (HBCT)) and repeated every four years (in the text below we refer to this as ‘community testing’). The three interventions are –1) Risk behaviour reduction for individuals newly diagnosed with HIV, 2) male circumcision for HIV uninfected men, and 3) ART initiation for HIV infected persons. A combination prevention intervention consists of the effects of these three interventions acting together in KZN population and we studied two possible combination interventions (
Assumed coverage levels of the community testing and the interventions were chosen to be optimistic but potentially achievable. Community testing increases the proportion of adults that ‘know’ their HIV status to 90%; new rounds of community testing are implemented every 4 years, allowing persons infected in the interim or not tested in previous rounds to learn their status. No testing is assumed to take place between the rounds of the four-yearly community testing and sensitivity analyses incorporated lower testing levels in each HIV testing. The model allows retesting individuals and tracks whether they have been infected since their last HIV test or remain uninfected (
(A) The individual impacts of risk reduction following HIV diagnosis (behaviour change), ART, and circumcision acting alone as single intervention components. ‘ART only’ designates initiating treatment at CD4 threshold of 350. (B) HIV incidence after implementation of ART initiation at CD4 count threshold of 200, 350, and at any CD4 count for all individuals that have been tested. All Interventions are assumed to commence in 2014. In this figure we assume counterfactually that individuals newly diagnosed with HIV do not reduce risk behaviour except in panel (A) in which the individual impact of risk reduction following HIV diagnosis is studied. Projections at year 15 are also displayed for comparison.
Current KZN circumcision prevalence (27%
HIV infected individuals who are aware of their HIV status are implicitly assumed to have regular CD4 count monitoring and thus access ART promptly after their CD4 cell count falls below a chosen threshold (two thresholds are modelled: former South Africa guideline to initiate ART at CD4 ≤ 200/mm3 and current South Africa and WHO guidelines, to initiate ART at CD4 ≤ 350 cells/mm3
Measuring the interaction between co-existing interventions: to tease out any interaction between the interventions
The combined interventions have interaction if
First, we disentangle the time variation of the impact of the three interventions mentioned above by having them acting alone in the population of KZN. Secondly, we estimate the joint impact when all of these interventions are in action (denoted as the “Combination I” intervention in
An uncertainty range for the key results is presented below between parentheses to reflect the uncertainties in calibrating model parameters to the epidemiological context of KZN. To reflect this uncertainty, model parameters that are difficult to estimate reliably are randomly selected, using prior distributions, from within credible limits based on local demographic data, reported indicators of sexual behaviour (
Here, we examine the impact of the individual interventions on HIV incidence at an early time point (four years after initial implementation); (
To disentangle the effect of ART from risk behaviour reduction among newly-identified HIV-infected adults (in
Different thresholds for ART initiation upon knowledge of status were explored further (
Next, we examine the impact of implementing all three components (reducing risk behaviour, male circumcision, and initiating ART at CD4 count of 350) in a combination intervention that is based on community testing (‘Combination I’ in
(
Finally, we investigate the impact of a combination intervention that includes expanded access to ART by initiating ART upon diagnosis (the ‘Combination II’ scenario). Under this scenario, the reduction in incidence would be greater than under Combination I at the short and long terms. At 4 years the reduction in incidence is 63% (60%–65%) versus 47% (43%–50%) for Combination I, and at 15 years the reduction in incidence is 76% (71%–81%) versus 52% (45%–60%) for Combination I (
(
The continuation of HIV community testing, immediate initiation of ART, and circumcision in Combination II intervention would achieve two major goals of HIV prevention interventions. First, the rate of new HIV infections would eventually be reduced to a low level: 0.3 new infections per 100 pyar after 25 years. Second, it would reduce the rate of HIV deaths and simultaneously bring the rate of new HIV infections below the rate of AIDS death - a point defined as the ‘AIDS Transition’
At high levels of coverage for the interventions, the interaction among them could lead to unneeded excessive protection; this is the case for example when large numbers of individuals are exposed to two interventions that reduce the same risk. Newly diagnosed individuals with HIV can be exposed to ART and risk reduction.
To show the synergy between ART and circumcision, the effects of risk behaviour reduction following HIV diagnosis (RBR) are ignored in calculating the dotted lines.
We mathematically modelled a combination prevention package based on the platform of testing 90% of adults in KwaZulu-Natal, South Africa through community HIV testing campaigns every four years coupled with risk behaviour reduction following HIV diagnosis, ART initiation for HIV-infected adults according to current WHO and South African guidelines at CD4 ≤ 350 cells/mm3, and male circumcision for HIV-uninfected men. The model is parameterized to the epidemiological context of KZN and includes important pragmatic assumptions about initiating treatment based on knowledge of HIV serostatus, repeating community testing every four years to identify newly-infected adults and those not previously tested, and assuming realistic drop-out rates from ART, suboptimal viral suppression due to imperfect adherence on ART, incomplete uptake of circumcision with coverage consistent with targets in the South Africa’s national plan, and modest and temporary changes in sexual risk behaviours following HIV testing
The combination of intervention components that act over different time scales with different impact on HIV incidence. The combined effects of these interventions reduce both the risk of acquisition and transmission of HIV, and could generate rapid, sustained, and substantial reductions in HIV incidence. Further, our results suggest that high coverage HIV testing every four years coupled with high uptake of circumcision and ART initiation upon HIV diagnosis could reduce HIV incidence and death rates to as low as 0.3% per year, significantly reducing the scale of the epidemic. By utilizing a measure for synergy we showed that although the effects of circumcision, ART, and risk behaviour reduction coexist in the population as a result of the combination intervention, the effects substantially strengthen each other particularly if the assumed levels of coverage for these interventions are maintained.
These findings have important implications for HIV prevention prioritization and program planning. Large reductions in HIV incidence in high prevalence settings in sub-Saharan Africa can be attained with ambitious, but feasible, assumptions about scale-up coverage and impact of HIV testing, male circumcision, and ART initiation and retention. Our assumed ambitious levels of coverage are premised on high coverage in pilot work and preliminary studies; HIV testing rates in large scale HBCT programs in Uganda and South Africa have exceeded 80%
We showed that maintaining high coverage levels of testing and risk reduction, circumcision, and HIV treatment would not compromise the synergy between these interventions. Optimizing the prevention benefits of each and every intervention of these to combat HIV is important due to the imperfections in the current HIV population-level intervention programs such as the suboptimal coverage and adherence levels, the drop out from ART, and the temporary nature of the reduction in sexual risk behaviour after HIV diagnoses.
We have not incorporated the impact of circumcision provision to HIV-infected men, because there is little evidence of direct effect of circumcision on HIV transmission to women
Although there have been other model projections suggesting single HIV interventions could achieve similar levels of impact, these have required more demanding assumptions such as universal testing every year and perfect adherence on ART that may not be consistently attainable
The rapid increase in the numbers of individuals in need of HIV care and circumcision services, in Combination I and II, demands parallel increases in the capacity and the accessibility of HIV care and circumcision clinics. A parallel increase in active follow up would also be required to achieve ART timely initiation, high circumcision uptake, and the sustainability of reduced risk behaviours. The waiting period between the four-yearly testing waves might facilitate task shifting to active follow up of persons newly diagnosed with HIV. We have not investigated the financial obligations and implications of any of our scenarios. Recent studies have illustrated that among non-traditional counselling and testing methods, door-to-door HIV counselling and testing in Ugandan population has the lowest cost
Our findings have significant implications for studies that aim to measure the impact of combination HIV prevention. First, the full impact of combination prevention interventions will be achieved over 10–15 years. Because most forms of impact evaluations of combination HIV prevention interventions, including community-randomized trials and programmatic assessments, are anticipated to examine impact over a much shorter period (e.g. 2–3 years), those studies could underestimate the full benefit of combination packages. Second, our model found that a determinant of short-term impact of a combination package is risk behaviour reduction following HIV diagnosis as a product of community testing. If the degree of risk reduction is less than we assumed, the ability to measure the impact on HIV incidence in a short-term evaluation is reduced. The time to see different effect magnitudes for individual components is an important consideration in the duration and interpretation of community-randomized trials of combination prevention, and argues for longer periods of observation, and monitoring intermediate biologic markers such as community viral load and key process outcomes such as number of men circumcised. The growing difference between the impacts of Combination I and Combination II over time indicates the importance of longer periods in comparing the effectiveness of different combination prevention packages. Lastly, the small relative differences in the impact of single interventions at the short-term (
Although the efficacy of topical or oral pre-exposure prophylaxis (PrEP) in reducing HIV risk has been demonstrated
The goal of this model was to evaluate the population-level impact on HIV incidence if high coverage levels of available strategies are achieved in KZN, South Africa. The numerical estimates presented are specific to KZN, and the impact of interventions in different contexts might vary. In settings where a lower proportion of men are already circumcised, the impact of the combination intervention could be greater and more sensitive to the uptake of circumcision. We have incorporated the uncertainty in identifying the epidemiological context of KZN using a rejection-sampling approach. Prioritizing interventions for specific age, gender, or demographic group was not the focus of this modelling exercise. Therefore, the model is not age-structured and has no details about how sexual partnerships are formed between members of different demographic groups
In summary, combination HIV prevention represents the best hope for a significant impact in reducing population HIV incidence in hyperendemic countries. These theoretical model results indicate that achieving high coverage of evidence-based combination HIV prevention interventions will have a greater population impact than any of the individual interventions, and could lead to large reductions in population HIV incidence in four years with increased impact thereafter. It is now time to implement this combination prevention approach in a high prevalence sub-Saharan setting, with a rigorous evaluation conducted with sufficient coverage levels and duration in order to assess the impact on population HIV incidence.
(DOC)
We thank Drs. Ann Kurth, Elioda Tumwesigye and Judy Wasserheit for useful discussion on these topics.