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Transmission patterns of HIV-subtypes A/AE versus B: inferring risk-behavior trends and treatment-efficacy limitations from viral genotypic data obtained prior to and during antiretroviral therapy.

Avidor B, Turner D, Mor Z, Chalom S, Riesenberg K, Shahar E, Pollack S, Elbirt D, Sthoeger Z, Maayan S, Olshtain-Pops K, Averbuch D, Chowers M, Istomin V, Anis E, Mendelson E, Ram D, Levy I, Grossman Z - PLoS ONE (2013)

Bottom Line: Treatment-failing, regimen-stratified subtype-A/AE- and B-patients differed from each other significantly in the frequencies of the major resistance-conferring mutations T215FY, K219QE and several secondary mutations.Notably, failing boosted protease-inhibitors (PI) treatment was not significantly associated with protease or RT mutations in either subtype.The phenomenon of treatment failure in boosted-PI-including regimens in the apparent absence of drug-resistance to any of the drugs, and its relation to adherence, require further investigation.

View Article: PubMed Central - PubMed

Affiliation: Crusaid Kobler AIDS Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

ABSTRACT

Background: HIV subtypes A and CRF01_AE (A/AE) became prevalent in Israel, first through immigration of infected people, mostly intravenous-drug users (IVDU), from Former Soviet-Union (FSU) countries and then also by local spreading. We retrospectively studied virus-transmission patterns of these subtypes in comparison to the longer-established subtype B, evaluating in particular risk-group related differences. We also examined to what extent distinct drug-resistance patterns in subtypes A/AE versus B reflected differences in patient behavior and drug-treatment history.

Methods: Reverse-transcriptase (RT) and protease sequences were retrospectively analyzed along with clinical and epidemiological data. MEGA, ClusalX, and Beast programs were used in a phylogenetic analysis to identify transmission networks.

Results: 318 drug-naive individuals with A/AE or patients failing combination antiretroviral therapy (cART) were identified. 61% were IVDU. Compared to infected homosexuals, IVDU transmitted HIV infrequently and, typically, only to a single partner. 6.8% of drug-naive patients had drug resistance. Treatment-failing, regimen-stratified subtype-A/AE- and B-patients differed from each other significantly in the frequencies of the major resistance-conferring mutations T215FY, K219QE and several secondary mutations. Notably, failing boosted protease-inhibitors (PI) treatment was not significantly associated with protease or RT mutations in either subtype.

Conclusions: While sizable transmission networks occur in infected homosexuals, continued HIV transmission among IVDU in Israel is largely sporadic and the rate is relatively modest, as is that of drug-resistance transmission. Deviation of drug-naive A/AE sequences from subtype-B consensus sequence, documented here, may subtly affect drug-resistance pathways. Conspicuous differences in overall drug-resistance that are manifest before regimen stratification can be largely explained in terms of treatment history, by the different efficacy/adherence limitations of older versus newer regimens. The phenomenon of treatment failure in boosted-PI-including regimens in the apparent absence of drug-resistance to any of the drugs, and its relation to adherence, require further investigation.

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Propagation and incidence rates of A/AE-HIV in Israel.A. Birth sites of individuals diagnosed with A/AE by year of diagnosis. (FSU – red squares; Israel – blue triangles). B. Infection site of individuals diagnosed with A/AE by year of diagnosis. (FSU – red squares; Israel – blue triangles). C. Birth site and infection place of A/AE-patients of specified transmission groups, by year of diagnosis. Red solid line – IVDU born and infected in FSU; dashed brown line – IVDU born in FSU and infected in Israel; green solid line – heterosexuals (mostly females) born in FSU and infected in Israel; light blue solid line – heterosexsuals born and infected in Israel; blue solid line – MSM born and infected in Israel. D. Newly-diagnosed IVDU infected in Israel (blue triangles) or in FSU (red circles) per-year as a fraction of the total number of A/AE-infected IVDU in the same year. Also shown are the total numbers of immigrants from FSU to Israel per-year (dashed line). FSU – Former Soviet Union; IVDU – Intravenous drug users; Is – Israel; MSM – Men who have sex with men.
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pone-0057789-g001: Propagation and incidence rates of A/AE-HIV in Israel.A. Birth sites of individuals diagnosed with A/AE by year of diagnosis. (FSU – red squares; Israel – blue triangles). B. Infection site of individuals diagnosed with A/AE by year of diagnosis. (FSU – red squares; Israel – blue triangles). C. Birth site and infection place of A/AE-patients of specified transmission groups, by year of diagnosis. Red solid line – IVDU born and infected in FSU; dashed brown line – IVDU born in FSU and infected in Israel; green solid line – heterosexuals (mostly females) born in FSU and infected in Israel; light blue solid line – heterosexsuals born and infected in Israel; blue solid line – MSM born and infected in Israel. D. Newly-diagnosed IVDU infected in Israel (blue triangles) or in FSU (red circles) per-year as a fraction of the total number of A/AE-infected IVDU in the same year. Also shown are the total numbers of immigrants from FSU to Israel per-year (dashed line). FSU – Former Soviet Union; IVDU – Intravenous drug users; Is – Israel; MSM – Men who have sex with men.

Mentions: Seventy-six percent of more than 300 infected immigrants from FSU whose HIV virus was genotyped carried A/AE viruses. Most of them were IVDU (Table 1). A/AE viruses started to be detected in considerable numbers in Israel in 1996–7 (Figure 1). Before 2004, the total number of A/AE carriers diagnosed in Israel each year and the number of those among them known to have been infected with A/AE-HIV in the FSU paralleled quite closely. This correlation was weakened later, as immigration from FSU declined and the fractions of MSM and non-IVDU heterosexuals among A/AE carriers progressively increased (Figure 1A). Since 2007, the numbers of newly diagnosed individuals infected with the A/AE viruses while in Israel exceeded the numbers of those who were infected in FSU (Figure 1B). Stratifying the data by risk groups (Figure 1C, Table 1) shows a number of interesting features. First, as IVDU who were infected in FSU were diagnosed at an increasing rate between 1999 and 2002, they started to increasingly infect other FSU-born IVDU in Israel, but hardly any others. Second, the numbers of heterosexuals diagnosed with A/AE viruses each year were on the rise only since 2007, and those were mainly FSU-born females infected in Israel (Figure 1C, Table 1). Third, only in 2008 did the virus start establishing itself rapidly among Israeli-born, and those infected were almost exclusively MSM (Figure 1C). Gay men diagnosed with A/AE who were born in FSU were also mostly infected in Israel (Table 1).


Transmission patterns of HIV-subtypes A/AE versus B: inferring risk-behavior trends and treatment-efficacy limitations from viral genotypic data obtained prior to and during antiretroviral therapy.

Avidor B, Turner D, Mor Z, Chalom S, Riesenberg K, Shahar E, Pollack S, Elbirt D, Sthoeger Z, Maayan S, Olshtain-Pops K, Averbuch D, Chowers M, Istomin V, Anis E, Mendelson E, Ram D, Levy I, Grossman Z - PLoS ONE (2013)

Propagation and incidence rates of A/AE-HIV in Israel.A. Birth sites of individuals diagnosed with A/AE by year of diagnosis. (FSU – red squares; Israel – blue triangles). B. Infection site of individuals diagnosed with A/AE by year of diagnosis. (FSU – red squares; Israel – blue triangles). C. Birth site and infection place of A/AE-patients of specified transmission groups, by year of diagnosis. Red solid line – IVDU born and infected in FSU; dashed brown line – IVDU born in FSU and infected in Israel; green solid line – heterosexuals (mostly females) born in FSU and infected in Israel; light blue solid line – heterosexsuals born and infected in Israel; blue solid line – MSM born and infected in Israel. D. Newly-diagnosed IVDU infected in Israel (blue triangles) or in FSU (red circles) per-year as a fraction of the total number of A/AE-infected IVDU in the same year. Also shown are the total numbers of immigrants from FSU to Israel per-year (dashed line). FSU – Former Soviet Union; IVDU – Intravenous drug users; Is – Israel; MSM – Men who have sex with men.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585963&req=5

pone-0057789-g001: Propagation and incidence rates of A/AE-HIV in Israel.A. Birth sites of individuals diagnosed with A/AE by year of diagnosis. (FSU – red squares; Israel – blue triangles). B. Infection site of individuals diagnosed with A/AE by year of diagnosis. (FSU – red squares; Israel – blue triangles). C. Birth site and infection place of A/AE-patients of specified transmission groups, by year of diagnosis. Red solid line – IVDU born and infected in FSU; dashed brown line – IVDU born in FSU and infected in Israel; green solid line – heterosexuals (mostly females) born in FSU and infected in Israel; light blue solid line – heterosexsuals born and infected in Israel; blue solid line – MSM born and infected in Israel. D. Newly-diagnosed IVDU infected in Israel (blue triangles) or in FSU (red circles) per-year as a fraction of the total number of A/AE-infected IVDU in the same year. Also shown are the total numbers of immigrants from FSU to Israel per-year (dashed line). FSU – Former Soviet Union; IVDU – Intravenous drug users; Is – Israel; MSM – Men who have sex with men.
Mentions: Seventy-six percent of more than 300 infected immigrants from FSU whose HIV virus was genotyped carried A/AE viruses. Most of them were IVDU (Table 1). A/AE viruses started to be detected in considerable numbers in Israel in 1996–7 (Figure 1). Before 2004, the total number of A/AE carriers diagnosed in Israel each year and the number of those among them known to have been infected with A/AE-HIV in the FSU paralleled quite closely. This correlation was weakened later, as immigration from FSU declined and the fractions of MSM and non-IVDU heterosexuals among A/AE carriers progressively increased (Figure 1A). Since 2007, the numbers of newly diagnosed individuals infected with the A/AE viruses while in Israel exceeded the numbers of those who were infected in FSU (Figure 1B). Stratifying the data by risk groups (Figure 1C, Table 1) shows a number of interesting features. First, as IVDU who were infected in FSU were diagnosed at an increasing rate between 1999 and 2002, they started to increasingly infect other FSU-born IVDU in Israel, but hardly any others. Second, the numbers of heterosexuals diagnosed with A/AE viruses each year were on the rise only since 2007, and those were mainly FSU-born females infected in Israel (Figure 1C, Table 1). Third, only in 2008 did the virus start establishing itself rapidly among Israeli-born, and those infected were almost exclusively MSM (Figure 1C). Gay men diagnosed with A/AE who were born in FSU were also mostly infected in Israel (Table 1).

Bottom Line: Treatment-failing, regimen-stratified subtype-A/AE- and B-patients differed from each other significantly in the frequencies of the major resistance-conferring mutations T215FY, K219QE and several secondary mutations.Notably, failing boosted protease-inhibitors (PI) treatment was not significantly associated with protease or RT mutations in either subtype.The phenomenon of treatment failure in boosted-PI-including regimens in the apparent absence of drug-resistance to any of the drugs, and its relation to adherence, require further investigation.

View Article: PubMed Central - PubMed

Affiliation: Crusaid Kobler AIDS Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

ABSTRACT

Background: HIV subtypes A and CRF01_AE (A/AE) became prevalent in Israel, first through immigration of infected people, mostly intravenous-drug users (IVDU), from Former Soviet-Union (FSU) countries and then also by local spreading. We retrospectively studied virus-transmission patterns of these subtypes in comparison to the longer-established subtype B, evaluating in particular risk-group related differences. We also examined to what extent distinct drug-resistance patterns in subtypes A/AE versus B reflected differences in patient behavior and drug-treatment history.

Methods: Reverse-transcriptase (RT) and protease sequences were retrospectively analyzed along with clinical and epidemiological data. MEGA, ClusalX, and Beast programs were used in a phylogenetic analysis to identify transmission networks.

Results: 318 drug-naive individuals with A/AE or patients failing combination antiretroviral therapy (cART) were identified. 61% were IVDU. Compared to infected homosexuals, IVDU transmitted HIV infrequently and, typically, only to a single partner. 6.8% of drug-naive patients had drug resistance. Treatment-failing, regimen-stratified subtype-A/AE- and B-patients differed from each other significantly in the frequencies of the major resistance-conferring mutations T215FY, K219QE and several secondary mutations. Notably, failing boosted protease-inhibitors (PI) treatment was not significantly associated with protease or RT mutations in either subtype.

Conclusions: While sizable transmission networks occur in infected homosexuals, continued HIV transmission among IVDU in Israel is largely sporadic and the rate is relatively modest, as is that of drug-resistance transmission. Deviation of drug-naive A/AE sequences from subtype-B consensus sequence, documented here, may subtly affect drug-resistance pathways. Conspicuous differences in overall drug-resistance that are manifest before regimen stratification can be largely explained in terms of treatment history, by the different efficacy/adherence limitations of older versus newer regimens. The phenomenon of treatment failure in boosted-PI-including regimens in the apparent absence of drug-resistance to any of the drugs, and its relation to adherence, require further investigation.

Show MeSH
Related in: MedlinePlus