The conventional strategy is to distribute antiretroviral drugs to people in every city and village.
The governments in the African region are considering providing antiretroviral drugs to people who do not have the virus but are at risk of contracting it.
Such drugs are known as pre-exposure prophylaxis, or PrEP.
"Since results from clinical trials have shown that antiretroviral drugs are effective in protecting individuals against HIV, the big question now is how best to use them," said Sally Blower from the University of California, Los Angeles (UCLA) in the US.
The researchers have developed the new strategy by using a complex mathematical model.
"The methods we developed can be used to find 'hot zones' in any other sub-Saharan countries that have geographic variation in the severity of their HIV epidemic, such as Lesotho, Botswana, Nigeria and Uganda," said the study's first author David Gerberry, a former UCLA postdoctoral fellow.
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In South Africa, where 17 percent of the population is infected with HIV, the model predicted that targeting hot zones would prevent 40 percent more infections than using the conventional strategy, the researchers said.
The new method will therefore be 40 percent more cost-effective.
To develop the strategy, researchers designed a computer model that calculated and mapped the incidence of HIV in South Africa and identified "hot zones".
The model revealed that two of South Africa's nine provinces are "hot zones".
"Our results are quite striking. Both strategies would provide PrEP to the same number of people, but using the 'hot zones' plan would prevent 40 percent more HIV infections than using the conventional plan," Blower said.
The report appeared in the journal Nature Communications.